Submissions for variant NM_017780.4(CHD7):c.6955C>T (p.Arg2319Cys)

dbSNP: rs121434341

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000224986	SCV000281760	pathogenic	CHARGE syndrome	2016-03-17	criteria provided, single submitter	research
Laboratoire de Genetique Biologique, CHU de Poitiers	RCV000224986	SCV000899230	pathogenic	CHARGE syndrome		criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000224986	SCV001208143	pathogenic	CHARGE syndrome	2024-12-26	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 2319 of the CHD7 protein (p.Arg2319Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with CHARGE syndrome (PMID: 16155193, 16763960, 18073582, 18484313, 21158681, 22033296, 28554332; Feretetal.ACMG2010Abstract#1671). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 235889). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt CHD7 protein function with a positive predictive value of 95%. This variant disrupts the p.Arg2319 amino acid residue in CHD7. Other variant(s) that disrupt this residue have been observed in individuals with CHD7-related conditions (PMID: 16400610), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001731455	SCV001983117	pathogenic	not provided	2024-01-02	criteria provided, single submitter	clinical testing	Published functional studies suggest this variant alters gene transcription (PMID: 31289371); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22539353, 21158681, 31729160, 16155193, 18484313, 16763960, 18073582, 31289371, 32914532, 22033296, 33442180, 32978145, 32804436, 34716235, 28554332, 36597107)
Baylor Genetics	RCV000224986	SCV004041515	pathogenic	CHARGE syndrome	2023-08-24	criteria provided, single submitter	clinical testing
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV000224986	SCV004805251	pathogenic	CHARGE syndrome	2024-06-29	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003417801	SCV004106228	pathogenic	CHD7-related disorder	2024-07-18	no assertion criteria provided	clinical testing	The CHD7 c.6955C>T variant is predicted to result in the amino acid substitution p.Arg2319Cys. This variant has been reported in individuals with CHARGE syndrome of variable severity (Table S1, Bergman et al. 2012. PubMed ID: 22539353; Table S1, Bowling et al. 2017. PubMed ID: 28554332; Table S2, Cheng et al. 2019. PubMed ID: 31729160; Table 1, Dosunmu and Castleberry. 2020. PubMed ID: 32914532; Holak et al. 2008. PubMed ID: 18484313; Table 2, Jongmans et al. 2006. PubMed ID: 16155193; Lee et al. 2020. PubMed ID: 33442180; Brajadenta et al. 2019. PubMed ID: 31289371; Wei et al. 2020. PubMed ID: 32978145). This variant has been confirmed de novo in five of these unrelated individuals (Table S1, Bowling et al. 2017. PubMed ID: 28554332; Brajadenta et al. 2019. PubMed ID: 31289371; Table S2, Cheng et al. 2019. PubMed ID: 31729160; Lee et al. 2020. PubMed ID: 33442180; Table 2, Wei et al. 2020. PubMed ID: 32804436). In one family this variant was observed in the mildly affected mother of the proband (Table 1, Figure 4, Lalani et al. 2006. PubMed ID: 16400610). In vitro experimental studies suggest this variant impacts protein function (Figure 4, Brajadenta et al. 2019. PubMed ID: 31289371). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic.