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Congenital Heart Defect v0.445 ERBB2 Eleanor Ludington gene: ERBB2 was added
gene: ERBB2 was added to Congenital Heart Defect. Sources: Literature
Mode of inheritance for gene: ERBB2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ERBB2 were set to 40329538
Phenotypes for gene: ERBB2 were set to Congenital heart disease - left ventricular outflow tract obstruction defects; MONDO:0005453
Review for gene: ERBB2 was set to AMBER
Added comment: A missense single-nucleotide variant in ERBB2 (chr17:39717377 C>T, NM_004448.4:c.1795C>T, p. Arg599Cys (GRCh38), rs369903296) was identified in 3 unrelated Finnish probands with left ventricular outflow tract obstruction defects.
- all 3 probands were familial cases with multiple affected family members
- all 3 probands had severe phenotypes (diagnosed either prenatally or in the first days of life)
- Proband of family 1: hypoplastic left heart syndrome (HLHS; including BAV, hypoplastic aortic arch, coarctation of the aorta, ASD, left superior vena cava)
- Proband of family 2: Shone's complex and VSD including aortic valve stenosis, mitral stenosis, coarctation of the aorta
- Proband of family 3: HLHS (including mitral valve stenosis, BAV, aortic valve stenosis, muscular VSD)

The variant segregated in affected family members of each proband who had other less severe congenital heart disease
- Family 1 grandfather - coarctation of the aorta
- Family 2 mother - coarctation of the aorta, BAV
- Family 3 mother - coarctation of the aorta, BAV
- Family 1 father - BAV
- Family 2 maternal grandfather - asymmetric aortic valve
The variant also segregated in two unaffected family members in family 2, suggesting reduced penetrance.

The variant is present in gnomAD with a total allele frequency of 0.00009372 in Finnish Europeans and 0.000004340 across all populations.

Supportive functional assays and a Zebrafish model was conducted.
Sources: Literature
Congenital Heart Defect v0.437 KCTD10 Bryony Thompson gene: KCTD10 was added
gene: KCTD10 was added to Congenital Heart Defect. Sources: Literature
Mode of inheritance for gene: KCTD10 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KCTD10 were set to 24705121; 24430697; 38489388; 40121532
Phenotypes for gene: KCTD10 were set to multiple congenital anomalies/dysmorphic syndrome MONDO:0019042, KCTD10-related
Review for gene: KCTD10 was set to GREEN
Added comment: Two unrelated probands with multiple congenital anomalies, both with abnormalities of the cardiovascular system and confirmed de novo novel missense variants (p.R248Q and p.N169S). There were also additional individuals (<5) in the GeneDx in-house database who didn’t consent to case-level publication with confirmed de novo missesne variants in KCTD10 and overlapping phenotypes (100% with abnormalities of the cardiovascular system). Other congenital anomalies of different organs systems were present in 33-67% of the individuals. Further elucidation of the phenotypes associated with this gene are required. Additionally, null mouse and zebrafish models suggest Kctd10 is critical for cardiovascular development and is involved in the regulation of brain development.
Sources: Literature
Congenital Heart Defect v0.425 RBFOX2 Zornitza Stark edited their review of gene: RBFOX2: Added comment: STRONG by ClinGen. At least 5 unrelated families and supportive zebrafish model.; Changed rating: GREEN; Changed phenotypes: Congenital heart disease MONDO:0005453, RBFOX2-related
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.
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
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
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
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
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