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Incidentalome v0.300 SS18L1 Zornitza Stark gene: SS18L1 was added
gene: SS18L1 was added to Incidentalome. Sources: Expert Review
Mode of inheritance for gene: SS18L1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SS18L1 were set to 25888396; 24360741; 23708140; 30976389
Phenotypes for gene: SS18L1 were set to amyotrophic lateral sclerosis (MONDO:0004976)
Review for gene: SS18L1 was set to AMBER
Added comment: ClinGen has curated as LIMITED:

There are 5 variants (one nonsense, three missense, and one in-frame del) that have been reported in 5 probands in 3 publications (PMIDs: 23708140, 24360741, 31522742) that are included in this curation, one of which was not scored due to the patient harboring a variant in another ALS-causing gene and a high minor allele frequency in population databases. ALS-associated SS18L1 variants are suggested to dysregulate neuronal function by inhibiting dendrite outgrowth and microglial activation through a dominant-negative mechanism, however there is an absence of functional data from primary tissue of SS18L1 mutation carriers. This gene-disease relationship is also supported by experimental evidence (mouse models, expression, and protein interactions; PMIDs: 30976389, 14716005, 23708140). CREST knockout (Crest +/− ) and Q394X knock-in mice generated through CRISPR/Cas9 system displayed deficits in motor coordination and partially recapitulated ALS phenotypes (PMID: 30976389). In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship.
Sources: Expert Review
Incidentalome v0.299 PKP2 Zornitza Stark Phenotypes for gene: PKP2 were changed from Arrhythmogenic right ventricular dysplasia 9, MIM# 609040 to Arrhythmogenic right ventricular dysplasia 9, MIM# 609040; Dilated cardiomyopathy, MONDO:0005021, PKP2-related
Incidentalome v0.297 PKP2 Zornitza Stark Mode of inheritance for gene: PKP2 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Incidentalome v0.296 PKP2 Zornitza Stark edited their review of gene: PKP2: Added comment: PMID: 30562116: reported 2 cases with hypoplastic left heart syndrome (HLHS) and features of noncompaction resulting from a homozygous truncating variant in the PKP2 gene (c.1211dup (p.Val406fsTer4). In the second pregnancy, additional features of fetal hydrops, HLHS, severe RVH, NC, multiple VSD were observed.

PMID: 35059364: reported a homozygous PKP2 variant, c.1511-1G>C, in an infant with neonatal onset of congestive heart failure owing to severe Left ventricular non-compaction (LVNC) and multiple muscular ventricular septal defect (VSD).

PMID: 38050058 reported biallelic loss of function variants in three cases with lethal form of dilated cardiomyopathy with excessive trabeculations (DCM-ET). In case 1, additional symptoms reported were micrognathia, retrognathia and hypertelorism. Case 2 had no extracardiac anomalies. In case 3, additional symptoms of hepatomegaly, supraventricular tachycardia consistent to Wolff Parkinson-White syndrome.; Changed publications: 30562116, 35059364, 38050058
Incidentalome v0.296 PKP2 Zornitza Stark edited their review of gene: PKP2: Changed phenotypes: Arrhythmogenic right ventricular dysplasia 9, MIM# 609040, Dilated cardiomyopathy, MONDO:0005021, PKP2-related; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Incidentalome v0.296 Zornitza Stark removed gene:FA2H from the panel
Incidentalome v0.295 CCNF Zornitza Stark edited their review of gene: CCNF: Changed rating: AMBER
Incidentalome v0.295 MLH1 Bryony Thompson Mode of inheritance for gene: MLH1 was changed from Unknown to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Incidentalome v0.287 LRRK2 Bryony Thompson Mode of pathogenicity for gene: LRRK2 was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Incidentalome v0.280 ITM2B Bryony Thompson Mode of pathogenicity for gene: ITM2B was changed from None to Other
Incidentalome v0.273 FUS Bryony Thompson Phenotypes for gene: FUS were changed from to Amyotrophic lateral sclerosis 6, with or without frontotemporal dementia, MIM# 608030
Incidentalome v0.270 FTL Bryony Thompson Phenotypes for gene: FTL were changed from to Neurodegeneration with brain iron accumulation 3, MIM# 606159
Incidentalome v0.263 CHMP2B Bryony Thompson Mode of pathogenicity for gene: CHMP2B was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Incidentalome v0.247 APP Bryony Thompson Mode of pathogenicity for gene: APP was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Incidentalome v0.232 POT1 Zornitza Stark Phenotypes for gene: POT1 were changed from Tumour predisposition with variety of solid and haematological malignancies reported. to Hereditary neoplastic syndrome, MONDO:0015356, POT1-related
Incidentalome v0.230 POT1 Zornitza Stark reviewed gene: POT1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Hereditary neoplastic syndrome, MONDO:0015356, POT1-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Incidentalome v0.230 POT1 Edward Chew gene: POT1 was added
gene: POT1 was added to Incidentalome. Sources: Expert list
Mode of inheritance for gene: POT1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: POT1 were set to (PMID:27528712; PMID: 29693246; PMID: 34769003; PMID: 36467798; PMID: 33216348; PMID: 24686849; PMID:24686846; PMID: 26403419; PMID: 32492864)
Phenotypes for gene: POT1 were set to Tumour predisposition with variety of solid and haematological malignancies reported.
Penetrance for gene: POT1 were set to Incomplete
Review for gene: POT1 was set to GREEN
Added comment: CLL (PMID: 27528712, published 2016) identified 4 families with POT1 variants and CLL.
Aberrant splicing of intron 13 (chromosome 7 g.124481233C.T/c.1164-1G.A) confirmed by RT-PCR. Missense p.Tyr36Cys and p.Gln376Arg predicted to be pathogenic by in silico methods. p.Gln358SerfsTer13 predicted to cause premature truncation.

Hodgkin Lymphoma (PMID: 29693246, published 2018) identified 2 families with POT1 variants and Hodgkin lymphoma.
p.Asp224Asn in 4 carriers with Hodgkin lymphoma. Variant validated functionally.
p.Tryp26His in 2 carriers with Hodgkin lymphoma. Some functional validation performed.

AML (PMID: 34769003, published 2021) identified p.Q199* in a 8yo with AML and monosomy 7. Unaffected father, de novo status of variant not confirmed. Some functional validation (but conflicting).

Multiple myeloma (PMID: 36467798, published 2022) looked at inherited predisposition for multiple myeloma. Identified 4 families with POT1 variants who have myeloma, thyroid cancer, and AML. Functional validation not performed.

Multiple haematological malignancies, cutaneous melanoma and solid cancers in a family from Queensland (PMID: 33216348, published 2020). The variant p.D224N has been reported and functionally validated by other authors.

Cutaneous melanoma (PMID: 24686849; PMID:24686846, published in same issue of journal in 2014) identified families with strong family history of melanoma. PMID: 24686849 identified 4 families with 4 different POT1 variants. PMID 24686846 identified 5 families with same founder p.Ser270Asn variant. Functional validation of pathogenicity performed in the 2 papers.

Li-Fraumeni Like syndrome (PMID: 26403419 published 2015) identified 3 families with p.R117C variant and strong family history of Li-Fraumeni Like syndrome. Variant functionally validated.

Medullary thyroid cancer (PMID: 32492864 published 2020) identified 1 family with p.V29L. The variant segregates with papillary thyroid cancer. Some functional validation performed.
Sources: Expert list
Incidentalome v0.230 UBQLN2 Sangavi Sivagnanasundram edited their review of gene: UBQLN2: Changed mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Incidentalome v0.230 UBQLN2 Sangavi Sivagnanasundram changed review comment from: Established gene identified in many individuals with ALS and/or dementia however there is conflicting evidence on the mode of pathogenicity.

PMID: 21857683 – 3 unrelated individuals with missense mutations (P497S, P509S, P525S) causative of UBQLN2- related ALS and ALS/Dementia.

PMID: 31319884 Reports on multiple articles conducting functional studies with evidence supporting that mutations in UBQLN2 impair the UPS pathway.

PMID: 26152284 – In vivo mouse model that showed that UBQLN2 mutants cause neurodegeneration and aggregate formation however the gene-disease association link wasn’t identified.

PMID: 25388785 – transgenic knockout rat model showed that mutant UBQLN2 cells lead to aggregation formation. Cresyl violet staining in the rats showed a reduction in neuron density which led to neurodegeneration. Neural impairment in the rats were confirmed by Golgi staining and was shown to have a distorted structure of cortex.; to: Established gene identified in many individuals with ALS and/or dementia however there is conflicting evidence on the mode of pathogenicity.

PMID: 21857683 – 3 unrelated individuals with missense mutations (P497S, P509S, P525S) causative of UBQLN2- related ALS and ALS/Dementia.

PMID: 31319884 Reports on multiple articles conducting functional studies with evidence supporting that mutations in UBQLN2 impair the UPS pathway.

PMID: 26152284 – In vivo mouse model that showed that UBQLN2 mutants cause neurodegeneration and aggregate formation however the gene-disease association link wasn’t identified.

PMID: 25388785 – transgenic knockout rat model showed that mutant UBQLN2 cells lead to aggregation formation. Cresyl violet staining in the rats showed a reduction in neuron density which led to neurodegeneration. Neural impairment in the rats were confirmed by Golgi staining and was shown to have a distorted structure of cortex.
Incidentalome v0.230 VAPB Sangavi Sivagnanasundram reviewed gene: VAPB: Rating: AMBER; Mode of pathogenicity: None; Publications: 18322265, 15372378, 23771029; Phenotypes: Amyotrophic lateral sclerosis 8 (MONDO:0012077, MIM 608627); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Incidentalome v0.230 VCP Sangavi Sivagnanasundram reviewed gene: VCP: Rating: GREEN; Mode of pathogenicity: None; Publications: 21145000, 33004675; Phenotypes: Frontotemporal dementia and/or Amyotrophic lateral sclerosis 6 (MONDO:0013501, MIM 613954), Inclusion body myopathy with early-onset Paget Disease and FTD [IBMPFD] (MONDO:0000507MIM 167320); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Incidentalome v0.230 Zornitza Stark removed gene:ACTC1 from the panel
Incidentalome v0.229 UBQLN2 Sangavi Sivagnanasundram reviewed gene: UBQLN2: Rating: AMBER; Mode of pathogenicity: None; Publications: 21857683, 31319884, 26152284, 25388785; Phenotypes: Amyotrophic lateral sclerosis 15, with or without frontotemporal dementia (MONDO: 0010459, MIM#300857); Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Incidentalome v0.229 TARDBP Sangavi Sivagnanasundram reviewed gene: TARDBP: Rating: GREEN; Mode of pathogenicity: Other; Publications: 18309045, 19609911; Phenotypes: Amyotrophic lateral sclerosis 10, with or without FTD, Frontotemporal lobar degeneration, TARDBP-related (MIM#612069, MONDO: 0012790); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Incidentalome v0.229 SORL1 Sangavi Sivagnanasundram reviewed gene: SORL1: Rating: RED; Mode of pathogenicity: Other; Publications: 17564960; Phenotypes: ; Mode of inheritance: Unknown
Incidentalome v0.229 SNCAIP Sangavi Sivagnanasundram reviewed gene: SNCAIP: Rating: RED; Mode of pathogenicity: None; Publications: 18366718; Phenotypes: ; Mode of inheritance: Unknown
Incidentalome v0.229 PSEN2 Sangavi Sivagnanasundram changed review comment from: Well established rare cause of Alzheimer Disease.

PMID: 10652366: In vitro functional assay shows that a mutation in the PSEN2 gene causes an effect to the endoproteolytic processing of the transmembrane protein thus a loss of function to the transmembrane protein.

PMID: 7638622: (Article refers to gene in previously terminology of STM2)
N141I founder mutation was identified in 20 individuals from 5 Volgan German families.
The point mutation is present in the conserved human and mouse homolog (S182).

PMID: 12925374: A spanish individual identified with a T430M mutation (a common variant reported in the Latino/Admixed American population but at a low frequency [PopMax AF 0.01%]).; to: Well established rare cause of Alzheimer Disease.

PMID: 10652366: In vitro functional assay shows that a mutation in the PSEN2 gene causes an effect to the endoproteolytic processing of the transmembrane protein thus a loss of function to the transmembrane protein.

PMID: 7638622: (Article refers to gene in previously terminology of STM2)
N141I founder mutation was identified in 20 individuals from 5 Volgan German families.
The point mutation is present in the conserved human and mouse homolog (S182).

PMID: 12925374: A spanish individual identified with a T430M mutation (a common variant reported in the Latino/Admixed American population but at a low frequency [PopMax AF 0.01%]).
Incidentalome v0.229 PSEN2 Sangavi Sivagnanasundram reviewed gene: PSEN2: Rating: GREEN; Mode of pathogenicity: None; Publications: 10652366, 7638622, 7651536, 12925374; Phenotypes: Alzheimer Disease type 4 (MONDO:0011743, MIM#606889); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Incidentalome v0.229 PSEN1 Sangavi Sivagnanasundram reviewed gene: PSEN1: Rating: GREEN; Mode of pathogenicity: Other; Publications: 20301340, 7596406, 16033913; Phenotypes: Alzheimer disease, type 3 (MONDO:0011913, MIM#607822); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Incidentalome v0.229 SCN1B Sangavi Sivagnanasundram reviewed gene: SCN1B: Rating: AMBER; Mode of pathogenicity: None; Publications: 9697698, 17020904, 12011299; Phenotypes: Generalized epilepsy with febrile seizures plus, type 1 (MONDO:0018214, MIM 604233); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Incidentalome v0.229 RBM12 Sangavi Sivagnanasundram reviewed gene: RBM12: Rating: AMBER; Mode of pathogenicity: Other; Publications: 28628109, 36711667; Phenotypes: Schizophrenia 19 (MIM#617629); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Incidentalome v0.227 PCSK9 Zornitza Stark Mode of inheritance for gene: PCSK9 was changed from Unknown to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Incidentalome v0.226 PCSK9 Sangavi Sivagnanasundram reviewed gene: PCSK9: Rating: GREEN; Mode of pathogenicity: Other; Publications: 24404629, 18354137, 12730697, 15654334, 16909389; Phenotypes: Familial Hypercholesterolemia 3 (MONDO:0011369, MIM# 603776), Low-density lipoprotein cholesterol level quantitative trait locus-1 (LDLCQ1, MIM# 603776); Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Incidentalome v0.226 PARK7 Sangavi Sivagnanasundram changed review comment from: Note that the gene was renamed from DJ1 to PARK7 (articles and OMIM reference our gene with previous name)

Variants in PARK7 (DJ1) gene are a rare cause of Parkinson Disease and is currently only reported in 3 individuals from 3 unrelated families.

PMID: 11462174; 11835383 – 2 individuals from 2 unrelated families with variants in DJ1 that were causative of Parkinson Disease.

PMID: 16240358 – 3 affected sibs from a consanguineous Italian family; to: Note that the gene was renamed from DJ1 to PARK7 (articles and OMIM reference our gene with previous name)

Variants in PARK7 (DJ1) gene are a rare cause of Parkinson Disease and is currently only reported in 3 individuals from 3 unrelated families.

PMID: 11462174; 11835383 – 2 individuals from 2 unrelated families with variants in DJ1 that were causative of Parkinson Disease.

PMID: 16240358 – 3 affected sibs from a consanguineous Italian family
Incidentalome v0.226 PARK7 Sangavi Sivagnanasundram reviewed gene: PARK7: Rating: AMBER; Mode of pathogenicity: None; Publications: 11462174, 11835383, 16240358, 20301402; Phenotypes: Parkinson Disease (MONDO:0005180, MIM: 606324); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Incidentalome v0.226 OPTN Sangavi Sivagnanasundram reviewed gene: OPTN: Rating: GREEN; Mode of pathogenicity: None; Publications: 20428114, 31838784, 27493188; Phenotypes: Amyotrophic lateral sclerosis 12 with or without frontotemporal dementia (MONDO: 0013264, MIM#613435); Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Incidentalome v0.226 LRRK2 Sangavi Sivagnanasundram reviewed gene: LRRK2: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 20301387, 17200152, 15541308, 16172858; Phenotypes: Parkinson Disease type 8 (MONDO:0005180, MIM#607060); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Incidentalome v0.223 FIG4 Sangavi Sivagnanasundram reviewed gene: FIG4: Rating: GREEN; Mode of pathogenicity: None; Publications: 19118816, 20301623; Phenotypes: Amyotrophic Lateral Sclerosis Type 11 (MONDO: 0012945, MIM#612577); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Incidentalome v0.223 VPS13A Sangavi Sivagnanasundram reviewed gene: VPS13A: Rating: GREEN; Mode of pathogenicity: None; Publications: 20301561, 12404112, 15824261, 12404112; Phenotypes: Chorea-acanthocytosis (MONDO: 0008695, MIM#200150); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Incidentalome v0.223 VPS13A Sangavi Sivagnanasundram Deleted their review
Incidentalome v0.223 VPS13A Sangavi Sivagnanasundram reviewed gene: VPS13A: Rating: GREEN; Mode of pathogenicity: None; Publications: 20301561, 12404112, 15824261, 12404112; Phenotypes: Chorea-acanthocytosis; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Incidentalome v0.223 XK Sangavi Sivagnanasundram reviewed gene: XK: Rating: GREEN; Mode of pathogenicity: None; Publications: 20301528, 17133513; Phenotypes: McLeod Syndrome with or without chronic granulomatous disease (MIM#300842); Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Incidentalome v0.223 CLU Sangavi Sivagnanasundram reviewed gene: CLU: Rating: RED; Mode of pathogenicity: Other; Publications: 19734903, 20301340; Phenotypes: Alzheimer's Disease (MIM#104300); Mode of inheritance: Unknown
Incidentalome v0.223 FA2H Sangavi Sivagnanasundram reviewed gene: FA2H: Rating: GREEN; Mode of pathogenicity: Other; Publications: 31135052, 29395073, 18463364, 19068277, 20104589; Phenotypes: Spastic Paraplegia (MIM#612319); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Incidentalome v0.223 CALHM1 Sangavi Sivagnanasundram changed review comment from: PMID:19472444 – Study to identify whether mutation sin CALHM1 had any correlation to Alzheimers Disease. Study showed no association between CALHM1 and Alzheimers Disease; to: PMID:19472444 – Study to identify whether mutations in CALHM1 had any correlation to Alzheimers Disease. Study showed no association between CALHM1 and Alzheimers Disease (AD)

No evidence showing correlation between CALHM1 mutations and AD
Incidentalome v0.223 CALHM1 Sangavi Sivagnanasundram reviewed gene: CALHM1: Rating: RED; Mode of pathogenicity: Other; Publications: 19472444; Phenotypes: ; Mode of inheritance: Unknown
Incidentalome v0.223 APP Sangavi Sivagnanasundram changed review comment from: PubMed: 17121991: transgenic mouse study identified that hypoxia increase BACE1 activity which resulted in a significant increase in the production of beta-amyloid in AD-related APP mutations. The study showed that hypoxia up-regulated Bace1 mRNA and increased deposition of beta proteins.

PMID: 1520398 – V717I variant identified in multiple members in a Canadian family of European decent with a dominant inheritance of Alzheimers disease
PMID: 15365148 – 1 family with 6 affected individuals over 3 generations with heterozygous mutations in APP gene – phenotypic features of Alzheimers. Individuals had MRI conducted showing multiple white matter infarcts along the long penetrating arteries
PubMed: 15668448 – two siblings in an African American family with distinctive features of early-onset AD with APP mutations
PMID: 1671712 - V717I mutation identified in 2 unrelated UK families with Alzheimers disease via a genetic linkage study
PMID: 1678058 – 2 individuals from 2 unrelated Japanese families with early onset Alzheimers disease via a genetic linkage study; to: PubMed: 17121991: transgenic mouse study identified that hypoxia increase BACE1 activity which resulted in a significant increase in the production of beta-amyloid in AD-related APP mutations. The study showed that hypoxia up-regulated Bace1 mRNA leading to an increased deposition of beta proteins.

PMID: 1520398 – V717I variant identified in multiple members in a Canadian family of European decent with a dominant inheritance of Alzheimers disease
PMID: 15365148 – 1 family with 6 affected individuals over 3 generations with heterozygous mutations in APP gene – phenotypic features of Alzheimers. Individuals had MRI conducted showing multiple white matter infarcts along the long penetrating arteries
PubMed: 15668448 – two siblings in an African American family with distinctive features of early-onset AD with APP mutations
PMID: 1671712 - V717I mutation identified in 2 unrelated UK families with Alzheimers disease via a genetic linkage study
PMID: 1678058 – 2 individuals from 2 unrelated Japanese families with early onset Alzheimers disease via a genetic linkage study
Incidentalome v0.223 APP Sangavi Sivagnanasundram reviewed gene: APP: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 17121991, 1520398, 15365148, 15668448, 1671712, 1678058; Phenotypes: Alzheimer's Disease (MIM#104300); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Incidentalome v0.223 ANG Sangavi Sivagnanasundram reviewed gene: ANG: Rating: GREEN; Mode of pathogenicity: None; Publications: 17886298, 16501576, 18087731, 20301623; Phenotypes: Amyotrophic Lateral Sclerosis (MONDO: 0012753, MIM#611895); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Incidentalome v0.223 ATP7B Sangavi Sivagnanasundram reviewed gene: ATP7B: Rating: GREEN; Mode of pathogenicity: None; Publications: 8298639, 9554743, 10790207, 7626145, 16133174; Phenotypes: Wilson Disease (MONDO:0010200, MIM #277900); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Incidentalome v0.223 ATP7B Sangavi Sivagnanasundram Deleted their review
Incidentalome v0.223 ATP7B Sangavi Sivagnanasundram reviewed gene: ATP7B: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 8298639, 9554743, 10790207, 7626145, 16133174; Phenotypes: Wilson Disease (MIM#277900); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Incidentalome v0.222 UCHL1 Zornitza Stark edited their review of gene: UCHL1: Changed phenotypes: Spastic paraplegia 79A, autosomal dominant, MIM# 620221, Spastic paraplegia 79, autosomal recessive, MIM# 615491, MONDO:0014209, Neurodegenerative disease, MONDO:0005559, UCHL1-related; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Incidentalome v0.221 CHEK2 Zornitza Stark Mode of inheritance for gene: CHEK2 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Incidentalome v0.220 CHEK2 Seb Lunke Mode of inheritance for gene: CHEK2 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Incidentalome v0.220 CHEK2 Zornitza Stark Mode of inheritance for gene: CHEK2 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Incidentalome v0.219 CHEK2 Lucy Spencer reviewed gene: CHEK2: Rating: GREEN; Mode of pathogenicity: None; Publications: 36529819; Phenotypes: Li-Fraumeni syndrome 2 (MIM#609265), {Breast cancer, susceptibility to} (MIM#114480), {Colorectal cancer, susceptibility to} (MIM#114500), {Prostate cancer, familial, susceptibility to} (MIM#176807); Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Incidentalome v0.217 WNK2 Melanie Marty gene: WNK2 was added
gene: WNK2 was added to Incidentalome. Sources: Literature
Mode of inheritance for gene: WNK2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: WNK2 were set to PMID: 36270769
Phenotypes for gene: WNK2 were set to Serrated polyposis syndrome
Review for gene: WNK2 was set to AMBER
Added comment: Germline variants identified in 15 patients (14 missense, 1 fs) diagnosed with serrated polyposis syndrome. Limited segregation studies in 2 families (1 sibling in each family). Functional studies suggested germline WNK2 variants affect protein function in the context of the MAPK pathway.
Sources: Literature
Incidentalome v0.216 UCHL1 Zornitza Stark Mode of inheritance for gene: UCHL1 was changed from Unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Incidentalome v0.215 UCHL1 Zornitza Stark reviewed gene: UCHL1: Rating: GREEN; Mode of pathogenicity: None; Publications: 23359680, 3340629, 28007905, 32656641, 29735986, 28007905, 35986737; Phenotypes: Spastic paraplegia 79, autosomal recessive, MIM# 615491, MONDO:0014209, Neurodegenerative disease, MONDO:0005559, UCHL1-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Incidentalome v0.213 APC Zornitza Stark reviewed gene: APC: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Adenomatous polyposis coli, MIM# 175100; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Incidentalome v0.210 A2M Zornitza Stark reviewed gene: A2M: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Alzheimer disease, MONDO:0004975; Mode of inheritance: None
Incidentalome v0.210 GPD1L Zornitza Stark edited their review of gene: GPD1L: Changed rating: RED
Incidentalome v0.208 CASQ2 Zornitza Stark Mode of inheritance for gene: CASQ2 was changed from Unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Incidentalome v0.207 CASQ2 Zornitza Stark reviewed gene: CASQ2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Ventricular tachycardia, catecholaminergic polymorphic, 2, MIM# 611938; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Incidentalome v0.202 SNTA1 Zornitza Stark reviewed gene: SNTA1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Long QT syndrome 12, MIM# 612955; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Incidentalome v0.194 KCNE2 Zornitza Stark reviewed gene: KCNE2: Rating: AMBER; Mode of pathogenicity: None; Publications: 31983240; Phenotypes: Long QT syndrome 6, MIM# 613693; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Incidentalome v0.193 KCNE1 Zornitza Stark Mode of inheritance for gene: KCNE1 was changed from Unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Incidentalome v0.192 KCNE1 Zornitza Stark edited their review of gene: KCNE1: Changed rating: GREEN; Changed phenotypes: Jervell and Lange-Nielsen syndrome 2, MIM# 612347, Long QT syndrome 5, MIM# 613695; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Incidentalome v0.190 KCNQ1 Zornitza Stark Mode of inheritance for gene: KCNQ1 was changed from Unknown to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Incidentalome v0.189 KCNQ1 Zornitza Stark reviewed gene: KCNQ1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Long QT syndrome 1, MIM# 192500, Short QT syndrome 2, MIM# 609621, Jervell and Lange-Nielsen syndrome, MIM# 220400, Atrial fibrillation, familial, 3, MIM# 607554; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Incidentalome v0.186 KCNH2 Zornitza Stark reviewed gene: KCNH2: Rating: GREEN; Mode of pathogenicity: None; Publications: 31983240; Phenotypes: Long QT syndrome 2, MIM# 613688, Short QT syndrome , MIM#1 609620; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Incidentalome v0.182 CACNB2 Zornitza Stark reviewed gene: CACNB2: Rating: RED; Mode of pathogenicity: None; Publications: 29959160; Phenotypes: Brugada syndrome 4, MIM# 611876; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Incidentalome v0.182 PRKAG2 Zornitza Stark Phenotypes for gene: PRKAG2 were changed from to Cardiomyopathy, hypertrophic 6, MIM# 600858; Glycogen storage disease of heart, lethal congenital, MIM# 261740
Incidentalome v0.179 PRKAG2 Zornitza Stark Deleted their comment
Incidentalome v0.179 PRKAG2 Zornitza Stark edited their review of gene: PRKAG2: Added comment: Variants associated with cardiomyopathy, conduction disease, and ventricular pre-excitation. More than 50 unrelated individuals reported. Can present with isolated HCM.; Changed publications: 15877279, 17667862, 32646569; Changed phenotypes: Cardiomyopathy, hypertrophic 6, MIM# 600858, Glycogen storage disease of heart, lethal congenital, MIM# 261740
Incidentalome v0.179 MYL3 Zornitza Stark Phenotypes for gene: MYL3 were changed from to Cardiomyopathy, hypertrophic, 8, MIM# 608751
Incidentalome v0.177 MYL3 Zornitza Stark Mode of inheritance for gene: MYL3 was changed from Unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Incidentalome v0.176 MYL3 Zornitza Stark reviewed gene: MYL3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Cardiomyopathy, hypertrophic, 8, MIM# 608751; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Incidentalome v0.176 MYL2 Zornitza Stark Phenotypes for gene: MYL2 were changed from to Myopathy, myofibrillar, 12, infantile-onset, with cardiomyopathy, MIM# 619424; Cardiomyopathy, hypertrophic, 10, MIM# 608758
Incidentalome v0.174 MYL2 Zornitza Stark Mode of inheritance for gene: MYL2 was changed from Unknown to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Incidentalome v0.173 MYL2 Zornitza Stark reviewed gene: MYL2: Rating: GREEN; Mode of pathogenicity: None; Publications: 23365102, 32453731; Phenotypes: Myopathy, myofibrillar, 12, infantile-onset, with cardiomyopathy, MIM# 619424, Cardiomyopathy, hypertrophic, 10, MIM# 608758; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Incidentalome v0.172 CACNA1C Zornitza Stark Phenotypes for gene: CACNA1C were changed from to Hypertrophic cardiomyopathy; congenital heart defects; conduction abnormalities; Timothy syndrome, MIM# 601005; Long QT syndrome 8, MIM# 618447
Incidentalome v0.169 CACNA1C Zornitza Stark changed review comment from: Association with HCM: Recurrent missense at position p.Arg518Cys/His observed in three families with complex cardiac phenotype including HCM. Digenic/trigenic inheritance postulated in other families.

Arrhythmia: definitive evidence for causality in Timothy syndrome but only moderate or limited evidence for isolated LQTS as reported in Circulation. 2020 Feb 11;141(6):418-428 PMID: 31983240, by the International, Multicentered LQTS ClinGen Working Group
Sources: Expert list; to: Association with HCM: Recurrent missense at position p.Arg518Cys/His observed in three families with complex cardiac phenotype including HCM. Digenic/trigenic inheritance postulated in other families.

Arrhythmia: definitive evidence for causality in Timothy syndrome but only moderate or limited evidence for isolated LQTS as reported in Circulation. 2020 Feb 11;141(6):418-428 PMID: 31983240, by the International, Multicentered LQTS ClinGen Working Group

DISPUTED for Brugada.

Sources: Expert list
Incidentalome v0.169 CACNA1C Zornitza Stark edited their review of gene: CACNA1C: Changed phenotypes: Hypertrophic cardiomyopathy, congenital heart defects, conduction abnormalities, Timothy syndrome, MIM# 601005, Long QT syndrome 8, MIM# 618447
Incidentalome v0.169 CACNA1C Zornitza Stark edited their review of gene: CACNA1C: Changed rating: GREEN
Incidentalome v0.169 CACNA1C Zornitza Stark changed review comment from: Association with HCM: Recurrent missense at position p.Arg518Cys/His observed in three families with complex cardiac phenotype including HCM. Digenic/trigenic inheritance postulated in other families.
Sources: Expert list; to: Association with HCM: Recurrent missense at position p.Arg518Cys/His observed in three families with complex cardiac phenotype including HCM. Digenic/trigenic inheritance postulated in other families.

Arrhythmia: definitive evidence for causality in Timothy syndrome but only moderate or limited evidence for isolated LQTS as reported in Circulation. 2020 Feb 11;141(6):418-428 PMID: 31983240, by the International, Multicentered LQTS ClinGen Working Group
Sources: Expert list
Incidentalome v0.169 CACNA1C Zornitza Stark changed review comment from: Recurrent missense at position p.Arg518Cys/His observed in three families with complex cardiac phenotype including HCM. Digenic/trigenic inheritance postulated in other families.
Sources: Expert list; to: Association with HCM: Recurrent missense at position p.Arg518Cys/His observed in three families with complex cardiac phenotype including HCM. Digenic/trigenic inheritance postulated in other families.
Sources: Expert list
Incidentalome v0.167 TTN Zornitza Stark Mode of inheritance for gene: TTN was changed from Unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Incidentalome v0.166 TTN Zornitza Stark changed review comment from: DEFINITIVE by ClinGen.; to: DEFINITIVE by ClinGen for DCM and myopathy.

MODERATE for tibial muscular dystrophy and myofibrillar myopathy.

LIMITED for HCM and ARVC.
Incidentalome v0.166 TTN Zornitza Stark edited their review of gene: TTN: Changed phenotypes: Cardiomyopathy, dilated, 1G, MIM#604145, Cardiomyopathy, familial hypertrophic, 9, MIM# 613765, Tibial muscular dystrophy, tardive, MIM#600334, Salih myopathy (MIM#611705), Muscular dystrophy, limb-girdle, type 2J, 608807; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Incidentalome v0.166 TPM1 Zornitza Stark Phenotypes for gene: TPM1 were changed from to Cardiomyopathy, dilated, 1Y, MIM# 611878; Cardiomyopathy, hypertrophic, 3, MIM# 115196
Incidentalome v0.163 TPM1 Zornitza Stark changed review comment from: Several families reported, including ones with extensive segregation evidence; functional data, including animal model.

MODERATE by ClinGen.; to: Several families reported, including ones with extensive segregation evidence; functional data, including animal model.

MODERATE by ClinGen for DCM.
DEFINITIVE for HCM.
Incidentalome v0.163 TPM1 Zornitza Stark edited their review of gene: TPM1: Changed phenotypes: Cardiomyopathy, dilated, 1Y, MIM# 611878, Cardiomyopathy, hypertrophic, 3, MIM# 115196; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Incidentalome v0.163 TNNT2 Zornitza Stark Phenotypes for gene: TNNT2 were changed from to Cardiomyopathy, dilated, 1D, MIM# 601494; Cardiomyopathy, hypertrophic, 2, MIM# 115195; Cardiomyopathy, familial restrictive, 3, MIM# 612422; Left ventricular noncompaction 6, MIM# 601494
Incidentalome v0.160 TNNT2 Zornitza Stark changed review comment from: DEFINITIVE by ClinGen, multiple families, functional data. The p.Lys210del variant is a recurrent pathogenic variant.; to: DEFINITIVE by ClinGen for DCM and HCM, multiple families, functional data. The p.Lys210del variant is a recurrent pathogenic variant.
Incidentalome v0.160 TNNT2 Zornitza Stark edited their review of gene: TNNT2: Changed publications: 33947203, 11106718, 20978592, 20031601, 15542288, 17556660, 30681346; Changed phenotypes: Cardiomyopathy, dilated, 1D, MIM# 601494, Cardiomyopathy, hypertrophic, 2, MIM# 115195, Cardiomyopathy, familial restrictive, 3, MIM# 612422, Left ventricular noncompaction 6, MIM# 601494
Incidentalome v0.160 TNNI3 Zornitza Stark Phenotypes for gene: TNNI3 were changed from to Cardiomyopathy, dilated, 1FF, MIM#613286; Cardiomyopathy, hypertrophic, 7, MIM# 613690; Cardiomyopathy, familial restrictive, MIM#1115210
Incidentalome v0.157 TNNI3 Zornitza Stark edited their review of gene: TNNI3: Changed publications: 22464770, 31568572, 19590045, 20215591, 21846512, 2226790, 30681346; Changed phenotypes: Cardiomyopathy, dilated, 1FF, MIM#613286, Cardiomyopathy, hypertrophic, 7, MIM# 613690
Incidentalome v0.157 SCN5A Zornitza Stark Phenotypes for gene: SCN5A were changed from to Long QT syndrome 3 (MIM#603830); Sick sinus syndrome 1, MIM# 608567; Ventricular fibrillation, familial, 1, MIM# 603829; Brugada syndrome 1, MIM# 601144; Heart block, progressive, type IA, MIM# 113900; Cardiomyopathy, dilated, 1E, MIM# 601154
Incidentalome v0.155 SCN5A Zornitza Stark edited their review of gene: SCN5A: Added comment: Variants in this gene are also associated with a range of arrhythmia disorders.; Changed phenotypes: Long QT syndrome 3 (MIM#603830), Sick sinus syndrome 1, MIM# 608567, Ventricular fibrillation, familial, 1, MIM# 603829, Brugada syndrome 1, MIM# 601144, Heart block, progressive, type IA, MIM# 113900
Incidentalome v0.154 MYH7 Zornitza Stark Phenotypes for gene: MYH7 were changed from to Cardiomyopathy, dilated, 1S, MIM# 613426; MONDO:0013262; Cardiomyopathy, hypertrophic, 1, MIM# 192600; Laing distal myopathy, MIM# 160500; Myopathy, myosin storage, autosomal dominant, MIM# 608358; Myopathy, myosin storage, autosomal recessive, MIM# 255160
Incidentalome v0.152 MYH7 Zornitza Stark Mode of inheritance for gene: MYH7 was changed from Unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Incidentalome v0.151 MYH7 Zornitza Stark edited their review of gene: MYH7: Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Incidentalome v0.151 MYH7 Zornitza Stark changed review comment from: DEFINITIVE by ClinGen, multiple families with segregation evidence and functional data.; to: DEFINITIVE by ClinGen for HCM and DCM, multiple families with segregation evidence and functional data.

Also multiple families reported with skeletal myopathies.
Incidentalome v0.151 MYH7 Zornitza Stark edited their review of gene: MYH7: Changed publications: 21483645, 30874888, 21846512, 30384889, 25935763, 24558114, 27000522, 31179125, 24119082, 27965028, 33947203, 30681346, 15322983; Changed phenotypes: Cardiomyopathy, dilated, 1S, MIM# 613426, MONDO:0013262, Cardiomyopathy, hypertrophic, 1, MIM# 192600, Laing distal myopathy, MIM# 160500, Myopathy, myosin storage, autosomal dominant, MIM# 608358, Myopathy, myosin storage, autosomal recessive, MIM# 255160
Incidentalome v0.151 MYBPC3 Zornitza Stark Phenotypes for gene: MYBPC3 were changed from to Cardiomyopathy, dilated, 1MM, MIM#615396; Cardiomyopathy, hypertrophic, 4, MIM# 115197
Incidentalome v0.150 MYBPC3 Zornitza Stark Mode of inheritance for gene: MYBPC3 was changed from Unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Incidentalome v0.149 MYBPC3 Zornitza Stark changed review comment from: Association with HCM is definitive.

No segregation or experimental data to support association with DCM. VOUS only in large cohorts.; to: Association with HCM is DEFINITIVE.

No segregation or experimental data to support association with DCM. VOUS only in large cohorts.
Incidentalome v0.149 MYBPC3 Zornitza Stark edited their review of gene: MYBPC3: Changed rating: GREEN; Changed phenotypes: Cardiomyopathy, dilated, 1MM, MIM#615396, Cardiomyopathy, hypertrophic, 4, MIM# 115197; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Incidentalome v0.149 ACTC1 Zornitza Stark Phenotypes for gene: ACTC1 were changed from to Cardiomyopathy, dilated, 1R, MIM# 613424; Cardiomyopathy, hypertrophic, 11, MIM# 612098; Atrial septal defect 5, MIM# 612794
Incidentalome v0.146 ACTC1 Zornitza Stark edited their review of gene: ACTC1: Added comment: LIMITED to MODERATE association with congenital heart disease.; Changed publications: 31430208, 30384889, 9563954, 14605248, 20600154, 26432839, 17947298, 31430208; Changed phenotypes: Cardiomyopathy, dilated, 1R, MIM# 613424, Cardiomyopathy, hypertrophic, 11, MIM# 612098, Atrial septal defect 5, MIM# 612794
Incidentalome v0.145 TMEM43 Zornitza Stark Phenotypes for gene: TMEM43 were changed from to Arrhythmogenic right ventricular dysplasia 5, MIM# 604400; Auditory neuropathy, autosomal dominant 3, MIM# 619832; Emery-Dreifuss muscular dystrophy 7 (MIM#614302)
Incidentalome v0.142 TMEM43 Zornitza Stark edited their review of gene: TMEM43: Added comment: Association with deafness: MODERATE, two multiplex families with missense variants.

Association with muscular dystrophy LIMITED to MODERATE:
PMID: 21391237 (2011): Different variants reported in 2 adults with EDMD-related myopathy. Ile91Val present in gnomad, 20 hets. Other variant, Glu85Lys, presented in gnomad (1 het)

PMID: 30311943 (2019): 1 EDMD family reported with the same Glu85Lys variant. Muscle disease suspected at age of 17 in one family member.; Changed publications: 18313022, 21214875, 23812740, 22725725, 24598986, 29980933, 34050020, 21391237, 30311943; Changed phenotypes: Arrhythmogenic right ventricular dysplasia 5, MIM# 604400, Auditory neuropathy, autosomal dominant 3, MIM# 619832, Emery-Dreifuss muscular dystrophy 7 (MIM#614302)
Incidentalome v0.142 RYR2 Zornitza Stark Phenotypes for gene: RYR2 were changed from to Ventricular tachycardia, catecholaminergic polymorphic, 1, MIM# 604772; Arrhythmogenic right ventricular dysplasia 2, MIM# 600996; Hypertrophic cardiomyopathy
Incidentalome v0.139 RYR2 Zornitza Stark changed review comment from: Gene-disease association assessed as REFUTED by ClinGen: 57 papers reviewed in the process. Some of the original variants were relatively often present in reference alleles from the gnomAD database, clear ARVD diagnosis was not provided, segregation information was not informative and/or CPVT was also present in the family. In a recent review it was also recognized that the observed phenotype in the original three publications that reported RYR2 variants in ARVD for the first time should be catecholamine-induced ventricular tachycardia rather than ARVD, and this gene is no longer considered as ARVD causing (29543670).; to: ARVC: gene-disease association assessed as REFUTED by ClinGen: 57 papers reviewed in the process. Some of the original variants were relatively often present in reference alleles from the gnomAD database, clear ARVD diagnosis was not provided, segregation information was not informative and/or CPVT was also present in the family. In a recent review it was also recognized that the observed phenotype in the original three publications that reported RYR2 variants in ARVD for the first time should be catecholamine-induced ventricular tachycardia rather than ARVD, and this gene is no longer considered as ARVD causing (29543670).
Incidentalome v0.139 RYR2 Zornitza Stark edited their review of gene: RYR2: Added comment: DEFINITVE for CPVT.

REFUTED for ARVC.

LIMITED for HCM.; Changed rating: GREEN; Changed publications: 11159936, 25041964, 29543670, 11208676, 12093772; Changed phenotypes: Ventricular tachycardia, catecholaminergic polymorphic, 1, MIM# 604772, Arrhythmogenic right ventricular dysplasia 2, MIM# 600996, Hypertrophic cardiomyopathy
Incidentalome v0.139 PKP2 Zornitza Stark Phenotypes for gene: PKP2 were changed from to Arrhythmogenic right ventricular dysplasia 9, MIM# 609040
Incidentalome v0.136 LMNA Zornitza Stark Phenotypes for gene: LMNA were changed from to Cardiomyopathy, dilated, 1A, MIM# 115200; Arrhythmogenic right ventricular cardiomyopathy; Lipodystrophy, familial partial, type 2, MIM# 151660; Emery-Dreifuss muscular dystrophy 2, MIM#181350; Mandibuloacral dysplasia 248370; Restrictive dermopathy, lethal 275210; Hutchinson-Gilford progeria 176670; Muscular dystrophy, congenital 613205
Incidentalome v0.134 LMNA Zornitza Stark Mode of inheritance for gene: LMNA was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Incidentalome v0.133 LMNA Zornitza Stark edited their review of gene: LMNA: Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Incidentalome v0.132 LMNA Zornitza Stark changed review comment from: Association between LMNA and ARVC has been rated as LIMITED by ClinGen: small number of families reported where only some of the individuals with the variants had convincing ARVC phenotype. Rated Amber on this panel more due to phenotypic overlap with DCM and arrhythmias arising in this context.
Sources: Expert list; to: Established association with multiple phenotypes.
Incidentalome v0.132 LMNA Zornitza Stark edited their review of gene: LMNA: Changed rating: GREEN; Changed phenotypes: Cardiomyopathy, dilated, 1A, MIM# 115200, Arrhythmogenic right ventricular cardiomyopathy, Lipodystrophy, familial partial, type 2, MIM# 151660, Emery-Dreifuss muscular dystrophy 2, MIM#181350, Mandibuloacral dysplasia 248370, Restrictive dermopathy, lethal 275210, Hutchinson-Gilford progeria 176670, Muscular dystrophy, congenital 613205
Incidentalome v0.132 DSP Zornitza Stark Phenotypes for gene: DSP were changed from to Arrhythmogenic right ventricular dysplasia 8, MIM# 607450; Dilated cardiomyopathy with woolly hair, keratoderma, and tooth agenesis, MIM# 615821; Cardiomyopathy, dilated, with woolly hair and keratoderma, MIM# 605676; Epidermolysis bullosa, lethal acantholytic, MIM# 609638
Incidentalome v0.130 DSP Zornitza Stark Mode of inheritance for gene: DSP was changed from Unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Incidentalome v0.129 DSP Zornitza Stark edited their review of gene: DSP: Added comment: Established gene-disease associations.; Changed phenotypes: Arrhythmogenic right ventricular dysplasia 8, MIM# 607450, Dilated cardiomyopathy with woolly hair, keratoderma, and tooth agenesis, MIM# 615821, Cardiomyopathy, dilated, with woolly hair and keratoderma, MIM# 605676, Epidermolysis bullosa, lethal acantholytic, MIM# 609638
Incidentalome v0.129 DSG2 Zornitza Stark Phenotypes for gene: DSG2 were changed from to Arrhythmogenic right ventricular dysplasia 10, MIM# 610193; Cardiomyopathy, dilated, 1BB, MIM# 612877
Incidentalome v0.127 DSG2 Zornitza Stark Mode of inheritance for gene: DSG2 was changed from Unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Incidentalome v0.126 DSG2 Zornitza Stark Deleted their comment
Incidentalome v0.126 DSG2 Zornitza Stark edited their review of gene: DSG2: Added comment: Assessed as LIMITED by ClinGen for mono-allelic variants and DCM:

Human genetic evidence supporting this gene-disease relationship includes one published definitive DCM case with truncating variant in DSG2 published by Garcia-Pavia et al (2011, PMID: 21859740). Of note, this person had limited ECG/arrhythmia phenotyping. Multiple other published variants have population frequencies which exclude them from scoring, as they are observed at a frequency higher than would be expected to have a pathogenic effect. In addition, this gene-disease association is supported by experimental evidence from postnatal DCM hearts showing reduced DSG2 signal in myocardium and other intercalated disc proteins were normal(Kessler et al, 2017, PMID: 28764973). In summary, there is limited evidence to support this gene-disease relationship.

Bi-allelic variants and DCM: three families reported, two with missense variants.

DEFINITIVE for ARVC.; Changed phenotypes: Arrhythmogenic right ventricular dysplasia 10, MIM# 610193, Cardiomyopathy, dilated, 1BB, MIM# 612877; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Incidentalome v0.126 DSC2 Zornitza Stark Phenotypes for gene: DSC2 were changed from to Arrhythmogenic right ventricular dysplasia 11, MIM# 610476; Arrhythmogenic right ventricular dysplasia 11 with mild palmoplantar keratoderma and woolly hair, MIM# 610476
Incidentalome v0.124 DSC2 Zornitza Stark Mode of inheritance for gene: DSC2 was changed from Unknown to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Incidentalome v0.122 THSD4 Zornitza Stark Tag cardiac tag was added to gene: THSD4.
Incidentalome v0.122 THSD4 Zornitza Stark Deleted their review
Incidentalome v0.119 TGFBR2 Zornitza Stark reviewed gene: TGFBR2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Loeys-Dietz syndrome 2 , MIM#610168; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Incidentalome v0.116 TGFBR1 Zornitza Stark reviewed gene: TGFBR1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Loeys-Dietz syndrome 1, MIM# 609192; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Incidentalome v0.115 MYLK Zornitza Stark Phenotypes for gene: MYLK were changed from to Aortic aneurysm, familial thoracic 7, MIM#613780; Megacystis-microcolon-intestinal hypoperistalsis syndrome, MIM#249210
Incidentalome v0.113 MYLK Zornitza Stark Mode of inheritance for gene: MYLK was changed from Unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Incidentalome v0.112 MYLK Zornitza Stark edited their review of gene: MYLK: Changed publications: 28602422
Incidentalome v0.112 MYLK Zornitza Stark edited their review of gene: MYLK: Added comment: Amber for bi-allelic variants and gastrointestinal neuromuscular disease:
PMID: 28602422;
- 3 affecteds from 2 consanguineous families. each family is homozygous for 1x fs and 1x splice (abnormal splicing proven).
- IHC of 1 affected showed no protein expression in intestine and bladder
- For both families, no cardiac problems were reported for the carrier parents.; Changed phenotypes: Aortic aneurysm, familial thoracic 7, MIM#613780, Megacystis-microcolon-intestinal hypoperistalsis syndrome, MIM#249210; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Incidentalome v0.112 MYH11 Zornitza Stark Phenotypes for gene: MYH11 were changed from to Visceral myopathy 2, MIM# 619350; Megacystis microcolon intestinal hypoperistalsis syndrome, autosomal recessive, MIM#619351; Aortic aneurysm, familial thoracic 4, MIM# 132900
Incidentalome v0.110 MYH11 Zornitza Stark Mode of inheritance for gene: MYH11 was changed from Unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Incidentalome v0.109 MYH11 Zornitza Stark reviewed gene: MYH11: Rating: GREEN; Mode of pathogenicity: None; Publications: 31944481; Phenotypes: Visceral myopathy 2, MIM# 619350, Megacystis microcolon intestinal hypoperistalsis syndrome, autosomal recessive, MIM#619351, Aortic aneurysm, familial thoracic 4, MIM# 132900; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Incidentalome v0.109 HCN4 Zornitza Stark Phenotypes for gene: HCN4 were changed from to Sick sinus syndrome 2, MIM# 163800; Aortopathy
Incidentalome v0.106 HCN4 Zornitza Stark reviewed gene: HCN4: Rating: GREEN; Mode of pathogenicity: None; Publications: 12750403, 15123648, 16407510, 17646576, 25145518; Phenotypes: Sick sinus syndrome 2, MIM# 163800; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Incidentalome v0.103 COL3A1 Zornitza Stark Phenotypes for gene: COL3A1 were changed from to Ehlers-Danlos syndrome, vascular type, MIM# 130050; Polymicrogyria with or without vascular-type EDS, MIM# 618343
Incidentalome v0.101 COL3A1 Zornitza Stark Mode of inheritance for gene: COL3A1 was changed from Unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Incidentalome v0.100 COL3A1 Zornitza Stark reviewed gene: COL3A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 28742248, 19455184, 25205403; Phenotypes: Ehlers-Danlos syndrome, vascular type, MIM# 130050, Polymicrogyria with or without vascular-type EDS, MIM# 618343; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Incidentalome v0.97 BGN Zornitza Stark edited their review of gene: BGN: Changed rating: GREEN; Changed phenotypes: Meester-Loeys syndrome, MIM# 300989, Spondyloepimetaphyseal dysplasia, X-linked, MIM# 300106; Changed mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Incidentalome v0.96 ACTA2 Zornitza Stark Phenotypes for gene: ACTA2 were changed from to Aortic aneurysm, familial thoracic 6, MIM# 611788; Multisystemic smooth muscle dysfunction syndrome, MIM# 613834
Incidentalome v0.93 ACTA2 Zornitza Stark reviewed gene: ACTA2: Rating: GREEN; Mode of pathogenicity: None; Publications: 30724374; Phenotypes: Aortic aneurysm, familial thoracic 6, MIM# 611788, Multisystemic smooth muscle dysfunction syndrome, MIM# 613834; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Incidentalome v0.90 MBD4 Chern Lim edited their review of gene: MBD4: Added comment: PMID:35460607: Biallelic loss-of-function germline variants in four families with five individuals with adenomatous colorectal polyposis, acute myeloid leukemia, and uveal melanoma.

PMID:35381620: A 37-year-old man presented with symptomatic anaemia and pancytopenia, a diagnosis of myelodysplastic syndrome with ring sideroblasts and multilineage dysplasia (MDS-RS-MLD) was made on bone marrow biopsy, patient has a homozygous missense variant in the germline.; Changed rating: GREEN
Incidentalome v0.89 MBD4 Chern Lim reviewed gene: MBD4: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID:35460607; Phenotypes: Adenomatous colorectal polyposis, acute myeloid leukemia, and uveal melanoma; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Incidentalome v0.89 Zornitza Stark removed gene:CACNA2D1 from the panel
Incidentalome v0.88 THSD4 Zornitza Stark Phenotypes for gene: THSD4 were changed from Thoracic aortic aneurysm and dissection (TAAD) to Aortic aneurysm, familial thoracic 12, MIM# 619825
Incidentalome v0.87 THSD4 Zornitza Stark edited their review of gene: THSD4: Changed phenotypes: Aortic aneurysm, familial thoracic 12, MIM# 619825
Incidentalome v0.87 ANXA11 Zornitza Stark Phenotypes for gene: ANXA11 were changed from Amytrophic lateral sclerosis 23 MIM#617839 to Inclusion body myopathy and brain white matter abnormalities, MIM# 619733; Amyotrophic lateral sclerosis 23, MIM# 617839
Incidentalome v0.85 ANXA11 Zornitza Stark reviewed gene: ANXA11: Rating: GREEN; Mode of pathogenicity: None; Publications: 34048612, 28469040; Phenotypes: Inclusion body myopathy and brain white matter abnormalities, MIM# 619733, Amyotrophic lateral sclerosis 23, MIM# 617839; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Incidentalome v0.81 WT1 Seb Lunke reviewed gene: WT1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Denys-Drash syndrome, MIM# 194080, Frasier syndrome, MIM#136680, Wilms tumor, type 1, MIM#194070, Nephrotic syndrome, type 4, MIM#256370; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Incidentalome v0.79 CACNA2D1 Daniel Flanagan reviewed gene: CACNA2D1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Incidentalome v0.79 Zornitza Stark removed gene:ALS2 from the panel
Incidentalome v0.77 FTDALS Bryony Thompson STR: FTDALS was added
STR: FTDALS was added to Incidentalome. Sources: Expert list
Mode of inheritance for STR: FTDALS was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for STR: FTDALS were set to 25577942; 21944779; 21944778
Phenotypes for STR: FTDALS were set to Frontotemporal dementia and/or amyotrophic lateral sclerosis 1 MIM#105550
Review for STR: FTDALS was set to GREEN
STR: FTDALS was marked as clinically relevant
Added comment: NG_031977​.1:g.5321GGGGCC[X]
Repeat expansion affects the protein degradation pathways and may contribute to TDP‐43 accumulation
Normal alleles: ≤25 G4C2 hexanucleotide repeat units generally considered normal
Pathogenic high-penetrance alleles: ≥60 G4C2 hexanucleotide repeat units are considered pathogenic
Note: The minimal size of a G4C2 pathogenic repeat is under debate: some studies consider repeats of >30 G4C2 hexanucleotide repeat units as pathogenic, whereas others use a cutoff of 60 G4C2 hexanucleotide repeat units.
Sources: Expert list
Incidentalome v0.76 C9orf72 Bryony Thompson Gene: c9orf72 has been removed from the panel.
Incidentalome v0.71 ANK2 Zornitza Stark reviewed gene: ANK2: Rating: RED; Mode of pathogenicity: None; Publications: 31983240; Phenotypes: Long QT syndrome 4, MIM# 600919; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Incidentalome v0.70 HD Bryony Thompson STR: HD was added
STR: HD was added to Incidentalome. Sources: Expert list
Mode of inheritance for STR: HD was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for STR: HD were set to 8458085; 20301482; 29325606
Phenotypes for STR: HD were set to Huntington disease MIM#143100
Review for STR: HD was set to GREEN
STR: HD was marked as clinically relevant
Added comment: NM_002111.8:c.52_54CAG[X]
Primary mechanism of disease is gain of function
Normal: ≤26 repeats
Intermediate: 27-35 repeats, no risk for proband but expansion possible in the next generation
Pathogenic (reduced penetrance): 36-39 repeats, proband at risk for HD but may not develop symptoms
Pathogenic (full penetrance): ≥40 repeats, development of HD with increased certainty assuming a normal life span
Sources: Expert list
Incidentalome v0.69 HTT Bryony Thompson Added comment: Comment on list classification: Included on the panel as an STR under HD
Incidentalome v0.69 HTT Bryony Thompson Gene: htt has been removed from the panel.
Incidentalome v0.68 NF2 Elena Savva reviewed gene: NF2: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 29409008; Phenotypes: Neurofibromatosis, type 2, MIM#101000, Meningioma, NF2-related, somatic, MIM#607174, Schwannomatosis, somatic, MIM#162091; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Incidentalome v0.68 Zornitza Stark removed gene:KCNJ5 from the panel
Incidentalome v0.66 MBD4 Zornitza Stark gene: MBD4 was added
gene: MBD4 was added to Incidentalome. Sources: Literature
Mode of inheritance for gene: MBD4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MBD4 were set to https://www.biorxiv.org/content/10.1101/2021.04.27.441137v1.full.pdf
Phenotypes for gene: MBD4 were set to AML and colorectal polyps; MBD4-associated neoplasia syndrome
Review for gene: MBD4 was set to AMBER
Added comment: Three individuals reported with bi-allelic LOF and rare combination of AML and adenomatous colorectal polyps.
Sources: Literature
Incidentalome v0.65 SNCB Eleanor Williams reviewed gene: SNCB: Rating: AMBER; Mode of pathogenicity: None; Publications: 33760043; Phenotypes: Dementia, Lewy body, OMIM:127750; Mode of inheritance: None
Incidentalome v0.62 HTT Zornitza Stark reviewed gene: HTT: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Huntington disease, MIM# 143100; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Incidentalome v0.62 HTT Eleanor Williams changed review comment from: PMID: 33432339 - Jung et al 2021 - further characterisation of the family previously reported in PMID: 27329733 (Rodan et al 2016) - using WGS they confirm they are the most likely cause of the LOMARS phenotype and clarify their locations as NM_002111.8(HTT): c.8157T>A (p.Phe2719Leu) and NM_002111.8(HTT)c.4469+1G>A (Note there are incorrect Clinvar entries). Functional studies show them each to be a hypomorphic mutation, resulting in severe deficiency of huntingtin in compound heterozygotes.

Still only 2 cases reported to date with biallelic LOF variants in HTT associated with the LOMARS phenotype although this study add further weight with some functional data.; to: PMID: 33432339 - Jung et al 2021 - further characterisation of the family previously reported in PMID: 27329733 (Rodan et al 2016) - using WGS they confirm they are the most likely cause of the LOMARS phenotype and clarify their locations as NM_002111.8(HTT): c.8157T>A (p.Phe2719Leu) and NM_002111.8(HTT)c.4469+1G>A (Note there are incorrect Clinvar entries). Functional studies show them each to be a hypomorphic mutation, resulting in severe deficiency of huntingtin in compound heterozygotes.

Still only 2 cases reported to date ((PMID: 27329733/33432339 and 26740508) with biallelic LOF variants in HTT associated with the LOMARS phenotype although this study add further weight with some functional data.
Incidentalome v0.62 HTT Eleanor Williams reviewed gene: HTT: Rating: AMBER; Mode of pathogenicity: None; Publications: 33432339, 27329733, 26740508; Phenotypes: Lopes-Maciel-Rodan syndrome OMIM:617435; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Incidentalome v0.62 UQCRC1 Zornitza Stark Phenotypes for gene: UQCRC1 were changed from Parkinson's disease to Parkinsonism with polyneuropathy, MIM# 619279
Incidentalome v0.61 UQCRC1 Zornitza Stark edited their review of gene: UQCRC1: Changed phenotypes: Parkinsonism with polyneuropathy, MIM# 619279
Incidentalome v0.61 NTHL1 Zornitza Stark Marked gene: NTHL1 as ready
Incidentalome v0.61 NTHL1 Zornitza Stark Gene: nthl1 has been classified as Green List (High Evidence).
Incidentalome v0.61 NTHL1 Zornitza Stark Classified gene: NTHL1 as Green List (high evidence)
Incidentalome v0.61 NTHL1 Zornitza Stark Gene: nthl1 has been classified as Green List (High Evidence).
Incidentalome v0.60 NTHL1 Zornitza Stark gene: NTHL1 was added
gene: NTHL1 was added to Incidentalome. Sources: Literature
Mode of inheritance for gene: NTHL1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NTHL1 were set to 33454955
Phenotypes for gene: NTHL1 were set to NTHL1-associated cancer syndrome
Review for gene: NTHL1 was set to GREEN
Added comment: More than 10 unrelated families reported with a hereditary cancer syndrome predisposing to adenomatous polyposis and colorectal cancer. Half of biallelic carriers also displayed multiple colonic or extra-colonic primary tumors, mainly breast, endometrium, urothelium, and brain tumours. For digestive cancers, average age at diagnosis was 56.2 years.
Sources: Literature
Incidentalome v0.59 THSD4 Zornitza Stark Marked gene: THSD4 as ready
Incidentalome v0.59 THSD4 Zornitza Stark Gene: thsd4 has been classified as Green List (High Evidence).
Incidentalome v0.59 THSD4 Zornitza Stark Classified gene: THSD4 as Green List (high evidence)
Incidentalome v0.59 THSD4 Zornitza Stark Gene: thsd4 has been classified as Green List (High Evidence).
Incidentalome v0.58 THSD4 Zornitza Stark gene: THSD4 was added
gene: THSD4 was added to Incidentalome. Sources: Literature
Mode of inheritance for gene: THSD4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: THSD4 were set to 32855533
Phenotypes for gene: THSD4 were set to Thoracic aortic aneurysm and dissection (TAAD)
Review for gene: THSD4 was set to GREEN
Added comment: 5 functional heterozygous variants in THSD4 (two lead to a premature termination codon) found in 5 families with TAAD. Variants segregated with disease in other family members. THSD4 encodes ADAMTSL6, a microfibril-associated protein that promotes fibrillin-1 matrix assembly. The THSD4 variants studied lead to haploinsufficiency or impaired assembly of fibrillin-1 microfibrils. Thsd4+/- mice showed progressive dilation of the thoracic aorta. Histologic examination of aortic samples from a patient carrying a THSD4 variant and from Thsd4+/- mice, revealed typical medial degeneration and diffuse disruption of extracellular matrix.
Sources: Literature
Incidentalome v0.57 CCNF Zornitza Stark Phenotypes for gene: CCNF were changed from amyotrophic lateral sclerosis with/without frontotemporal dementia to Frontotemporal dementia and/or amyotrophic lateral sclerosis 5, MIM# 619141
Incidentalome v0.56 CCNF Zornitza Stark reviewed gene: CCNF: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Frontotemporal dementia and/or amyotrophic lateral sclerosis 5, MIM# 619141; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Incidentalome v0.55 UQCRC1 Zornitza Stark gene: UQCRC1 was added
gene: UQCRC1 was added to Incidentalome. Sources: Literature
Mode of inheritance for gene: UQCRC1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: UQCRC1 were set to 33141179; 33248804
Phenotypes for gene: UQCRC1 were set to Parkinson's disease
Review for gene: UQCRC1 was set to AMBER
Added comment: Three unrelated families reported in PMID 33141179 with some functional data, however PMID 33248804 failed to identify significant variants in this gene in a large PD cohort.
Sources: Literature
Incidentalome v0.51 NF2 Zornitza Stark reviewed gene: NF2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurofibromatosis, type 2, MIM# 101000; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Incidentalome v0.51 NF2 Eleanor Williams reviewed gene: NF2: Rating: ; Mode of pathogenicity: None; Publications: 33075808; Phenotypes: ; Mode of inheritance: None
Incidentalome v0.48 SNCA Zornitza Stark reviewed gene: SNCA: Rating: GREEN; Mode of pathogenicity: None; Publications: 32849182, 26858591, 32740728; Phenotypes: Dementia, Lewy body (MIM#127750), Parkinson disease 1 (MIM#168601), Parkinson disease 4 (MIM#605543); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Incidentalome v0.47 RAD51D Elena Savva gene: RAD51D was added
gene: RAD51D was added to Incidentalome. Sources: Literature
Mode of inheritance for gene: RAD51D was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: RAD51D were set to PMID: 28646019; 31937788; 26057125
Phenotypes for gene: RAD51D were set to {Breast-ovarian cancer, familial, susceptibility to, 4} 614291
Review for gene: RAD51D was set to GREEN
Added comment: Pure cancer susceptibility gene, no relationship found with germline mutations and other mendelian disease.
Sources: Literature
Incidentalome v0.45 GLA Zornitza Stark Mode of pathogenicity for gene: GLA was changed from to Other
Incidentalome v0.44 GLA Zornitza Stark Mode of inheritance for gene: GLA was changed from Unknown to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Incidentalome v0.43 GLA Elena Savva reviewed gene: GLA: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 8878432, 31613176; Phenotypes: Fabry disease 301500, Fabry disease, cardiac variant 301500; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Incidentalome v0.43 TUBA4A Zornitza Stark Phenotypes for gene: TUBA4A were changed from to Amyotrophic lateral sclerosis 22 with or without frontotemporal dementia, MIM# 616208
Incidentalome v0.39 TUBA4A Zornitza Stark reviewed gene: TUBA4A: Rating: AMBER; Mode of pathogenicity: None; Publications: 28069311, 25374358, 26675813; Phenotypes: Amyotrophic lateral sclerosis 22 with or without frontotemporal dementia, MIM# 616208; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Incidentalome v0.35 SNCB Zornitza Stark reviewed gene: SNCB: Rating: RED; Mode of pathogenicity: None; Publications: 15365127, 20697047; Phenotypes: Dementia, Lewy body, MIM#127750; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Incidentalome v0.35 PTEN Arina Puzriakova reviewed gene: PTEN: Rating: ; Mode of pathogenicity: None; Publications: 32588888; Phenotypes: Skewed immune repertoire composition; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Incidentalome v0.34 DNAJC7 Zornitza Stark gene: DNAJC7 was added
gene: DNAJC7 was added to Incidentalome. Sources: Literature
Mode of inheritance for gene: DNAJC7 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DNAJC7 were set to 31768050
Phenotypes for gene: DNAJC7 were set to amyotrophic lateral sclerosis
Review for gene: DNAJC7 was set to AMBER
Added comment: Two cohort studies in ALS patients identified 11 and 1 patient, respectively, with variants in DNAJC7. Seven of these are putative PTVs. No segregation or functional data. A small number of individuals with LOF variants are present in gnomad albeit less than expected. Given these are cohort studies, and an adult-onset condition, potentially of variable penetrance, we have taken a cautious approach and rated Amber for now.
Sources: Literature
Incidentalome v0.32 BAP1 Zornitza Stark gene: BAP1 was added
gene: BAP1 was added to Incidentalome. Sources: Expert list
Mode of inheritance for gene: BAP1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: BAP1 were set to 21941004; 23684012; 21874000; 21874003
Phenotypes for gene: BAP1 were set to Tumor predisposition syndrome, MIM# 614327
Review for gene: BAP1 was set to GREEN
Added comment: Generally adult onset, high-risk for the development of a variety of tumors, including benign melanocytic tumors as well as several malignant tumors, including uveal melanoma, cutaneous melanoma, malignant mesothelioma on exposure to asbestos, and other cancer types, such as lung adenocarcinoma, meningioma, and renal cell carcinoma
Sources: Expert list
Incidentalome v0.27 AKAP9 Zornitza Stark reviewed gene: AKAP9: Rating: RED; Mode of pathogenicity: None; Publications: 31983240; Phenotypes: Long QT syndrome 11, MIM# 611820; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Incidentalome v0.20 GPD1L Zornitza Stark reviewed gene: GPD1L: Rating: AMBER; Mode of pathogenicity: None; Publications: 17967977, 19666841; Phenotypes: Brugada syndrome 2, MIM# 611777; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Incidentalome v0.19 NR4A2 Zornitza Stark reviewed gene: NR4A2: Rating: RED; Mode of pathogenicity: None; Publications: 12756136, 9092472; Phenotypes: ; Mode of inheritance: None
Incidentalome v0.16 SMAD3 Melanie Marty reviewed gene: SMAD3: Rating: GREEN; Mode of pathogenicity: None; Publications: 21217753, 30661052; Phenotypes: Loeys-Dietz syndrome 3 613795; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Incidentalome v0.15 CCNF Bryony Thompson gene: CCNF was added
gene: CCNF was added to Incidentalome. Sources: Expert list
Mode of inheritance for gene: CCNF was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CCNF were set to 27080313; 31577344
Phenotypes for gene: CCNF were set to amyotrophic lateral sclerosis with/without frontotemporal dementia
Review for gene: CCNF was set to GREEN
Added comment: >3 families/cases and supporting functional evidence
Sources: Expert list
Incidentalome v0.13 ANXA11 Bryony Thompson gene: ANXA11 was added
gene: ANXA11 was added to Incidentalome. Sources: Expert list
Mode of inheritance for gene: ANXA11 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ANXA11 were set to 28469040; 29845112; 30109997
Phenotypes for gene: ANXA11 were set to Amytrophic lateral sclerosis 23 MIM#617839
Review for gene: ANXA11 was set to GREEN
Added comment: 4 different missense variants in 10 patients from 7 unrelated families with amyotrophic lateral sclerosis and functional assays supporting association.
Sources: Expert list
Incidentalome v0.10 CHCHD2 Bryony Thompson gene: CHCHD2 was added
gene: CHCHD2 was added to Incidentalome. Sources: Expert list
Mode of inheritance for gene: CHCHD2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CHCHD2 were set to 32068847; 25662902; 31600778
Phenotypes for gene: CHCHD2 were set to Parkinson disease 22, autosomal dominant MIM#616710
Review for gene: CHCHD2 was set to GREEN
Added comment: Adult-onset neurodegenerative disorder. Five families with heterozygous variants, segregation evidence for T61I in multiple families. Supporting functional evidence suggesting mitochondrial dysfunction through the genes role in mitochondrial respiratory function.
Sources: Expert list
Incidentalome v0.8 DDX41 Zornitza Stark gene: DDX41 was added
gene: DDX41 was added to Incidentalome. Sources: Expert list
Mode of inheritance for gene: DDX41 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: DDX41 were set to {Myeloproliferative/lymphoproliferative neoplasms, familial (multiple types), susceptibility to} MIM# 616871
Review for gene: DDX41 was set to GREEN
Added comment: Adult-onset disorder, often initially presents with myelodysplasia +/- a range of haematological malignancies. Reduced penetrance.
Sources: Expert list
Incidentalome v0.5 RABL3 Sue White gene: RABL3 was added
gene: RABL3 was added to Incidentalome_VCGS. Sources: Literature
Mode of inheritance for gene: RABL3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RABL3 were set to 31406347
Phenotypes for gene: RABL3 were set to pancreatic carcinoma
Penetrance for gene: RABL3 were set to unknown
Review for gene: RABL3 was set to GREEN
Added comment: germline truncating variants associated with increased risk of pancreatic carcinoma
Sources: Literature
Incidentalome v0.3 TRIM28 Zornitza Stark gene: TRIM28 was added
gene: TRIM28 was added to Incidentalome_VCGS. Sources: Literature
Mode of inheritance for gene: TRIM28 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TRIM28 were set to 30694527
Phenotypes for gene: TRIM28 were set to Wilm's tumour
Review for gene: TRIM28 was set to GREEN
Added comment: Eleven individuals with germline variants identified; plus one somatic. Exome sequencing on eight tumor DNA samples from six individuals showed loss-of-heterozygosity (LOH) of the TRIM28-locus by mitotic recombination in seven tumors, suggesting that TRIM28 functions as a tumor suppressor gene in Wilms tumor development.
Sources: Literature
Incidentalome v0.1 CHEK2 Zornitza Stark gene: CHEK2 was added
gene: CHEK2 was added to Incidentalome_VCGS. Sources: Other
Mode of inheritance for gene: CHEK2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: CHEK2 were set to Breast cancer
Review for gene: CHEK2 was set to GREEN
Added comment: Sources: Other
Incidentalome v0.0 TH Zornitza Stark gene: TH was added
gene: TH was added to Incidentalome_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: TH was set to Unknown