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| Congenital Heart Defect v0.339 | BRAF | Zornitza Stark Marked gene: BRAF as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Congenital Heart Defect v0.339 | BRAF | Zornitza Stark Gene: braf has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Congenital Heart Defect v0.339 | BRAF | Zornitza Stark Phenotypes for gene: BRAF were changed from to Cardiofaciocutaneous syndrome, 115150; Noonan syndrome 7, 613706 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Congenital Heart Defect v0.338 | BRAF | Zornitza Stark Publications for gene: BRAF were set to | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Congenital Heart Defect v0.337 | BRAF | Zornitza Stark Mode of pathogenicity for gene: BRAF 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 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Congenital Heart Defect v0.336 | BRAF | Zornitza Stark Mode of inheritance for gene: BRAF was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Congenital Heart Defect v0.315 | BRAF |
Penny Snell changed review comment from: Well established gene-disease association. Cardiofaciocutaneous and Noonan syndromes present with overlapping clinical features, including congenital heart defects. There is limited evidence for loss-of-function as a mechanism of disease for either of these phenotypes.; to: Well established gene-disease association. Cardiofaciocutaneous and Noonan syndromes present with overlapping clinical features, including congenital heart defects. There is limited evidence for loss-of-function as a mechanism of disease for either of these phenotypes. |
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| Congenital Heart Defect v0.315 | BRAF | Penny Snell reviewed gene: BRAF: 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: PMID: 19206169, 18042262; Phenotypes: Cardiofaciocutaneous syndrome, 115150, Noonan syndrome 7, 613706; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Congenital Heart Defect v0.315 | WASHC5 |
Lucas Mitchell gene: WASHC5 was added gene: WASHC5 was added to Congenital Heart Defect. Sources: ClinGen,Literature Mode of inheritance for gene: WASHC5 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: WASHC5 were set to PMID: 24065355; 37840956; 30896870; 32349777; 32349777 Phenotypes for gene: WASHC5 were set to Ritscher-Schinzel syndrome - MIM#220210; Ventricular septal defect; Atrial septal defect; Tetralogy of Fallot; Double outlet right ventricle; Hypoplastic left heart; Aortic stenosis; Pulmonic stenosis Penetrance for gene: WASHC5 were set to unknown Review for gene: WASHC5 was set to AMBER Added comment: Homozygous/biallelic variants in WASHC5 (previous name KIAA0196) are associated with Ritscher-Schinzel syndrome (RSS) - A developmental malformation syndrome characterised by craniofacial abnormalities, congenital heart defects, and cerebellar brain malformations. Cardiac defects include septal defects and aortic stenosis, among others (OMIM: Leonardi et al., 2001; Elliott et al., 2013). Victor Chang CHD gene registry reports on WASHC5, also stating unknown penetrance. (https://chdgene.victorchang.edu.au/gene/9897) Literature (humans): Elliot et al, 2013 (24065355) 8 first nations patients, and 8 of their parents, and 5 unaffected people from same geographic region (northern Manitoba, Canada) underwent homozygosity mapping by SNP array and sanger sequencing. Variable phenotypic traits among affected members included atrial and ventricular septal defects. The only biallelic mutations identified occurred in KIAA0196 (WASHC5), where sequence analysis revealed homozygosity for three novel variants (c.3335+2T>A, c.3335 +4C>A and c.3335+8A>G) in each patient (figure 2A). All parents were heterozygous for the three sequence changes, and none of the five control subjects was homozygous for any of these changes. Comparison of normalised cycle threshold (Ct) values indicated a 6.98 to 8.72 (mean 7.85)-fold reduction in the relative amount of KIAA0196 transcript in the patient samples versus the control sample. Sanger sequencing of the cloned PCR product from a patient revealed that the primary product did not contain exon 27 (figure 2B). Suggesting altered KIAA0196 transcript produced by the patient might be targeted for nonsense mediated decay. Strumpellin, the product of KIAA0196, is a highly conserved glycoprotein from plants to humans, and ubiquitously expressed. Harvey et al, 2023 (37840956), reports 2 probands with WASHC5 variants and CHD phenotype. Not clear if probands related, or from same geographical area. Zygosity not clear. No information provided about probands, family testing/segregation. Landis 2023, (37681527) a cohort of 1362 with CHD, reports one with variant in WASHC5. No further information provided about variant, zygosity, or about participant in paper or supp data. Bu. 2020 et al, (30896870) Reports, 9mnth male in Changsha, China, with patent ductus arteriosus (PDA) - an opening between two blood vessels leading from the heart, patent foramen ovale (PFO) - hole between the left and right atria, and KIAA0196 (WASHC5) variant. No mention zygosity or biallelic. No supp data provided. Møller Nielsen, 2021(https://doi.org/10.1016/j.ijcchd.2021.100164), Danish cohort study with Atrial septal defects (ASD), 384 variants identified, three WASHC5 variants are considered pathogenic. Supplementary table 3 reports three WASHC5 variants, but no further information is provided about participants, zygosity of variants, or if blood-related. Limitations state only had singleton data and unable to clarify inheritance/de-novo. Supplementary table reported further info for the three WASHC5 variants, but no explicit mention if biallelic mutations. Excel column J reports 'reads (Ref:Alt)' and indicates participants are ?heterozygous variants which may conflict with RSS being a recessive/biallelic condition? Hseih, 2020, (32349777) Mentioned having two damaging germline and one mosaic mutations in their cohort that supports WASHC5 to be a candidate CHD gene. No further information about those variants or participants is provided. No supp data provided. Animal models: Mouse Genome Informatics MGI#2146110) : Homozygous knockout mice die well prior to E13.5 as no evidence of conceptus. In heterozygous knockout mice no cardiovascular defect recorded. Bu, 2020 (32417190) Mouse and zebrafish studies show potential evidence for WASHC5 biallelic variants cause CHD/. However CliniGen Commented "neither provide evidence to support the gene-disease relationship (Bu et al., PMID:32417190)" In summary, Elliot et al provides detailed evidence, however looking further at recent literature, studies mention or report on WASHC5 variants and possible associations with CHD, but do not report enough detail to be confident and satisfy ClinGene/PanelApp criteria. Sources: ClinGen, Literature |
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| Congenital Heart Defect v0.192 | AL117258.1 |
Melanie Marty gene: AL117258.1 was added gene: AL117258.1 was added to Congenital Heart Defect. Sources: Literature Mode of inheritance for gene: AL117258.1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: AL117258.1 were set to 34903892 Phenotypes for gene: AL117258.1 were set to Heterotaxy; congenital heart defects Review for gene: AL117258.1 was set to GREEN Added comment: Gene also known as CIROP and LMLN2 Homozygous or compound heterozygous CIROP variants identified in 12 families with congenital heart defects associated with heterotaxy. Functional tests performed on Xenopus and zebrafish embryos showed that CIROP was essential for left side symmetry and is expressed in ciliated left–right organisers. Sources: Literature |
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| Congenital Heart Defect v0.163 | MIB1 |
Zornitza Stark changed review comment from: Established congenital cardiac disease gene. PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio study from the Deciphering Developmental Disorders study. 11 de novo variants (1 frameshift, 2 missense, 2 splice acceptor, 1 splice donor, 5 stopgain) identified in ~10,000 cases with developmental disorders (no other phenotype info provided). Sources: Expert Review; to: Li 2018 (PMID: 30322850): - in 4 CHD patients: p.Q237H (gv2v3 absent), p.W271G (gv2v3 absent), p.S520R (v2 5 hets) and p.T312Kfs*55 (NMD-pred, absent but many comparables in gnomAD). - HEK293T cells transfection studies showed: T312Kfs*55 and W271G strongly impaired MIB1 function on substrate ubiquitination, while Q237H and S520R had slight or no obvious changes. Interaction between MIB1 and JAG1 is severely interrupted by p.T312Kfs*55 and p.W271G, but not really in the other 2 missense. - Overexpression of wt or mutant in zebrafish all resulted in dysmorphic pheno, therefore not informative. PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio study from the Deciphering Developmental Disorders study. 11 de novo variants (1 frameshift, 2 missense, 2 splice acceptor, 1 splice donor, 5 stopgain) identified in ~10,000 cases with developmental disorders (no other phenotype info provided). Sources: Expert Review |
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| Congenital Heart Defect v0.131 | BCL9L |
Krithika Murali gene: BCL9L was added gene: BCL9L was added to Congenital Heart Defect. Sources: Expert list,Literature,Other Mode of inheritance for gene: BCL9L was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: BCL9L were set to 23035047; 8757136 Phenotypes for gene: BCL9L were set to Congenital Heart Disease; Heterotaxy Review for gene: BCL9L was set to AMBER Added comment: Novel gene disease association. Saunders et al. 2012 (PMID: 23035047) report biallelic BCL9L variants in 2 affected brothers with heterotaxy and congenital heart disease, heterozygous in unaffected parents. Functional evidence in zebrafish (PMID 8757136) Sources: Expert list, Literature, Other |
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| Congenital Heart Defect v0.0 | BRAF |
Zornitza Stark gene: BRAF was added gene: BRAF was added to Congenital Heart Defect_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services Mode of inheritance for gene: BRAF was set to Unknown |
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