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| Hypertrophic cardiomyopathy_HCM v0.169 | RPS6KB1 |
Zornitza Stark gene: RPS6KB1 was added gene: RPS6KB1 was added to Hypertrophic cardiomyopathy_HCM. Sources: Literature Mode of inheritance for gene: RPS6KB1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: RPS6KB1 were set to 34916228 Phenotypes for gene: RPS6KB1 were set to Hypertrophic cardiomyopathy, MONDO:0005045, RPS6KB1-related Review for gene: RPS6KB1 was set to GREEN Added comment: Jain et al. 2022 (PMID: 34916228) reported on two unrelated HCM families with the same heterozygous missense RPS6KB1 variant (p.G47W), and subsequently three further unrelated probands with HCM harbouring distinct heterozygous variants (p.Q49K, p.Y62H, respectively). Variants segregated with disease, were predicted pathogenic by silico analyses and were ultrarare or absent in population databases. Functional studies in the HL-1 (mouse cardiomyocytes) cells showed that the patient-specific RPS6KB1 mutant significantly increased cell size and activated rpS6 and ERK1/2 signalling cascades. The relationship between RPS6KB1 and cardiac hypertrophy has also been explored in feline and mice models (PMID: 15226426; 17976640) Sources: Literature |
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| Hypertrophic cardiomyopathy_HCM v0.163 | TULP3 |
Anna Ritchie commented on gene: TULP3: 15 individuals from eight unrelated families with bi-allelic variants in TULP3 were detected. The affected individuals reported are mostly adults, in the 3rd through 7th decades of life, and presented with progressive degenerative liver fibrosis with variable fibrocystic kidney disease and hypertrophic cardiomyopathy. The human phenotype was ecapitulated in adult zebrafish and confirmed disruption of critical ciliary cargo composition in several primary cell lines derived from affected individuals. |
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| Hypertrophic cardiomyopathy_HCM v0.163 | TULP3 |
Anna Ritchie edited their review of gene: TULP3: Added comment: 15 individuals from eight unrelated families with bi-allelic variants in TULP3 were detected. The affected individuals reported are mostly adults, in the 3rd through 7th decades of life, and presented with progressive degenerative liver fibrosis with variable fibrocystic kidney disease and hypertrophic cardiomyopathy. The human phenotype was ecapitulated in adult zebrafish and confirmed disruption of critical ciliary cargo composition in several primary cell lines derived from affected individuals.; Changed rating: GREEN |
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| Hypertrophic cardiomyopathy_HCM v0.162 | TULP3 |
Anna Ritchie gene: TULP3 was added gene: TULP3 was added to Hypertrophic cardiomyopathy_HCM. Sources: Literature Mode of inheritance for gene: TULP3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TULP3 were set to PMID: 35397207 Phenotypes for gene: TULP3 were set to progressive degenerative liver fibrosis with variable fibrocystic kidney disease; hypertrophic cardiomyopathy MONDO:0005045 Added comment: 15 individuals from eight unrelated families with bi-allelic variants in TULP3 were detected. The affected individuals reported are mostly adults, in the 3rd through 7th decades of life, and presented with progressive degenerative liver fibrosis with variable fibrocystic kidney disease and hypertrophic cardiomyopathy. The human phenotype was ecapitulated in adult zebrafish and confirmed disruption of critical ciliary cargo composition in several primary cell lines derived from affected individuals Sources: Literature |
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| Hypertrophic cardiomyopathy_HCM v0.159 | GYG1 |
Zornitza Stark gene: GYG1 was added gene: GYG1 was added to Hypertrophic cardiomyopathy_HCM. Sources: Expert Review Mode of inheritance for gene: GYG1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: GYG1 were set to 27718144; 20357282; 31628455 Phenotypes for gene: GYG1 were set to Hypertrophic Cardiomyopathy Review for gene: GYG1 was set to AMBER Added comment: 4 unrelated patients described in these reports with homozygous/compound het mutations in GYG1. All had a form of HCM, with extensive scarring, arrhythmia. Histological studies reveal storage of glycogen & polyglycosan associated with mutated glycogenin 1 within cardiac myocytes. The 3 patients in PMID 27718144 did not have overt skeletal myopathy. Other patients with mutations in this gene have had skeletal myopathy without cardiomyopathy. The cause for this variable expression is not entirely clear. The sister of one patient carried the homozygous mutation, but was asymptomatic. Well established gene-disease association with glycogen storage disorder, primarily affecting skeletal muscle. Sources: Expert Review |
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| Hypertrophic cardiomyopathy_HCM v0.158 | NEBL | Bryony Thompson Added comment: Comment on list classification: Limited gene-disease vailidity, Classification - 09/25/2020 by ClinGen Dilated Cardiomyopathy GCEP. Evidence Summary: NEBL was evaluated for autosomal dominant dilated cardiomyopathy (DCM). Human genetic evidence supporting this gene-disease relationship includes case-level data. Arimura and colleagues (2000, PMID: 11140941) analyzed 83 DCM patients and 311 healthy controls, identifying 4 missense variants of unknown significance (VUSs) in 4 DCM cases. High minor allele frequencies (MAFs) and lack of segregation excluded these variants as evidence. Purevjav and colleagues (2010, PMID: 20951326) investigated a total of 260 DCM patients and 300 unrelated ethnic matched controls by direct DNA sequencing. Authors identified 4 missense VUSs. One of these variants (Q128R) was downgraded in level of evidence due to the lack of segregation. The other 3 variants were not scored because of their MAF. Perrot and colleagues (2016, PMID: 27186169) investigated a total of 389 patients with DCM, HCM, or LVNC, 320 Caucasian sex-matched controls and 192 Caucasian sex-matched blood donors and identified 3 missense VUSs in 4 families. One of these variants was also carried by healthy relatives and therefore was excluded, however this may be explained by reduced penetrance. The 2 other variants lacked segregation as well and therefore were also excluded. In addition, this gene-disease association is supported by animal models. Mastronotaro and colleagues (2015, PMID: 25987543) created a NEBL knockout mice that exhibited normal cardiac function up to 9 months of age but after 2 weeks of transaortic constriction (TAC), these mice showed Z-line widening since the age of 5 months and upregulation of cardiac stress genes (basal and after TAC) However, absence of clinical DCM features in KO-NEBL mice as well as Western Blot analysis which contradicted previous findings by showing a similar protein expression between knockout and wild-type mice, excluding it as evidence. Purevjav and colleagues (2010, PMID: 20951326) generated a transgenic mouse overexpressing WT or mutant NEBL under the control of the α-MyHC promoter (4 variants were tested). Mice overexpressing p.K60N or p.Q128R variants died within 1 year because of severe heart enlargement and heart failure. Mice overexpressing p.G202R or p.A592E were born and developed normally but after 6 months displayed reduced stress tolerance, cardiac enlargement due to left ventricle dilation, myocyte disarray, and interstitial cell infiltration. In summary, there is limited evidence to support this gene-disease relationship. More evidence is needed to support the relationship of NEBL and autosomal dominant DCM. This classification was approved by the ClinGen Dilated Cardiomyopathy Working Group on October 11, 2019 (SOP Version 7). Gene Clinical Validity Standard Operating Procedures (SOP) - SOP7 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hypertrophic cardiomyopathy_HCM v0.89 | MT-TI |
Paul De Fazio changed review comment from: PMID: 12767666 2 families with maternally inherited HCM, variants were homoplasmic in tested affecteds (m.4300A>G) PMID: 30025578 1 family with HCM, variant was homoplasmic (m.4300A>G) PMID: 29481798 Homoplasmic m.4318-4322delC in one family with DCM and mitochondrial DNA depletion PMID: 23332932 Describe the morphologic, biochemical, and molecular features of hearts from 3 transplanted patients from 2 families (2x m.4300A>G, 1x m.4277C>T) with HCM. Seems to be an association with HCM but also possibly DCM? Not sure if this belongs on this panel. The HCM in the literature appears to be isolated. Sources: Literature; to: PMID: 12767666 2 families with maternally inherited HCM, variants were homoplasmic in tested affecteds (m.4300A>G) PMID: 30025578 1 family with HCM, variant was homoplasmic (m.4300A>G) PMID: 29481798 Homoplasmic m.4318-4322delC in one family with DCM and mitochondrial DNA depletion, other mtDNA abnormalities were also identified in this family. PMID: 23332932 Describe the morphologic, biochemical, and molecular features of hearts from 3 transplanted patients from 2 families (2x m.4300A>G, 1x m.4277C>T) with HCM. Seems to be an association with HCM but also possibly DCM? Not sure if this belongs on this panel. The HCM in the literature appears to be isolated. Sources: Literature |
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| Hypertrophic cardiomyopathy_HCM v0.89 | MT-TI |
Paul De Fazio changed review comment from: PMID: 12767666 2 families with maternally inherited HCM, variants were homoplasmic in tested affecteds (m.4300A>G) PMID: 30025578 1 family with HCM, variant was homoplasmic (m.4300A>G) PMID: 29481798 Homoplasmic m.4318-4322delC in one family with DCM and mitochondrial DNA depletion Seems to be an association with HCM but also DCM and other mito-related phenotypes? Sources: Literature; to: PMID: 12767666 2 families with maternally inherited HCM, variants were homoplasmic in tested affecteds (m.4300A>G) PMID: 30025578 1 family with HCM, variant was homoplasmic (m.4300A>G) PMID: 29481798 Homoplasmic m.4318-4322delC in one family with DCM and mitochondrial DNA depletion PMID: 23332932 Describe the morphologic, biochemical, and molecular features of hearts from 3 transplanted patients from 2 families (2x m.4300A>G, 1x m.4277C>T) with HCM. Seems to be an association with HCM but also possibly DCM? Not sure if this belongs on this panel. The HCM in the literature appears to be isolated. Sources: Literature |
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| Hypertrophic cardiomyopathy_HCM v0.57 | DES | Zornitza Stark Marked gene: DES as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hypertrophic cardiomyopathy_HCM v0.57 | DES | Zornitza Stark Gene: des has been classified as Red List (Low Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hypertrophic cardiomyopathy_HCM v0.57 | DES | Zornitza Stark Phenotypes for gene: DES were changed from to Hypertrophic cardiomyopathy; Dilated cardiomyopathy; Myofibrillar myopathy; ARVC | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hypertrophic cardiomyopathy_HCM v0.56 | DES | Zornitza Stark Mode of inheritance for gene: DES was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hypertrophic cardiomyopathy_HCM v0.55 | DES | Zornitza Stark Mode of inheritance for gene: DES was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hypertrophic cardiomyopathy_HCM v0.55 | DES | Zornitza Stark Mode of inheritance for gene: DES was changed from Unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hypertrophic cardiomyopathy_HCM v0.54 | DES | Zornitza Stark Classified gene: DES as Red List (low evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hypertrophic cardiomyopathy_HCM v0.54 | DES | Zornitza Stark Gene: des has been classified as Red List (Low Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hypertrophic cardiomyopathy_HCM v0.28 | DES | Ivan Macciocca reviewed gene: DES: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: arrhythmogenic right ventricular cardiomyopathy, myofibrillar myopathy 1, dilated cardiomyopathy; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hypertrophic cardiomyopathy_HCM v0.19 | NEBL |
Zornitza Stark gene: NEBL was added gene: NEBL was added to Hypertrophic cardiomyopathy_HCM. Sources: Literature Mode of inheritance for gene: NEBL was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: NEBL were set to 27186169 Phenotypes for gene: NEBL were set to Hypertrophic cardiomyopathy; dilated cardiomyopathy Review for gene: NEBL was set to GREEN Added comment: 7 individuals from 6 unrelated families described with missense variants in this gene; some with HOCM, some with DCM. Sources: Literature |
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| Hypertrophic cardiomyopathy_HCM v0.0 | DES |
Zornitza Stark gene: DES was added gene: DES was added to Hypertrophic cardiomyopathy_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services Mode of inheritance for gene: DES was set to Unknown |
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