Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001386200 | SCV001586339 | pathogenic | not provided | 2021-09-07 | criteria provided, single submitter | clinical testing | |
| New York Genome Center | RCV004554861 | SCV005044150 | likely pathogenic | Snijders Blok-Campeau syndrome | 2022-10-08 | criteria provided, single submitter | clinical testing | The de novo c.2656C>G, p.(His886Asp) variant identified in CHD3 substitutes a very well conserved Histidine with Aspartic Acid at amino acid 886/2001 (exon 16/40). This variant is absent from population databases (gnomADv2.1, gnomADv3.1.2, BRAVO-TOPMed Freeze 8, All of Us) suggesting it is not a common benign variant in the populations represented in those databases. The CHD3 gene is constrained against benign missense variation (Missense z-score=6.15), as well as loss of function variation (pLI=1). In silico algorithms predict this variant to be Pathogenic (REVEL; score:0.9649) to the function of the canonical transcript. The p.His886 residue is within the Helicase ATP-binding domain of CHD3 [PMID:30397230, 32483341]. This variant is reported as Pathogenic in ClinVar (VarID:1073248, 1 star, 1 submission), and two additional variants at the same amino acid (p.(His886Tyr); VarID:1333400 and p.(His886Arg); VarID:549729) are reported as Likely Pathogenic. While the p.(His886Asp) variant identified here has not been reported in affected individuals in the literature, a different amino acid change at the same position (p.(His886Arg)) has been reported in 3 independent affected individuals in the literature [PMID:30397230, 32483341, 33571694]. Given its absence in population databases, observation de novo here, in silico prediction of pathogenicity, and the presence of a different pathogenic variant at the same amino acid position, the c.2656C>G, p.(His886Asp) variant identified is reported as Likely Pathogenic. |