Submissions for variant NM_017780.4(CHD7):c.4787A>G (p.Asp1596Gly)

dbSNP: rs1057521078

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000426210	SCV000520955	likely pathogenic	not provided	2016-11-09	criteria provided, single submitter	clinical testing	The D1596G variant in the CHD7 gene has been reported previously in the heterozygous state in multiple unrelated individuals with CHARGE syndrome (Jongmans et al., 2006; Vuorela et al., 2007; de Arriba Munoz et al., 2011; Beate et al., 2012). The D1596G variant was not observed in approximately 6000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The D1596G variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties, and occurs at a position that is conserved across species. As an alternate mechanism, multiple in silico algorithms predict that c.4787 A>G (aka D1596G) might create a cryptic donor site in intron 21 which may supplant the natural donor site. Functional studies in zebrafish suggest that D1596G is a hypomorphic allele capable of rescuing the CHD7-morpholino phenotype (Balasubramanian et al., 2014). Therefore, we interpret D1596G as a likely pathogenic variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001865337	SCV002199530	uncertain significance	CHARGE syndrome	2021-04-10	criteria provided, single submitter	clinical testing	This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of CHARGE syndrome (PMID: 21196067, 16155193). ClinVar contains an entry for this variant (Variation ID: 381566). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CHD7 protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This sequence change replaces aspartic acid with glycine at codon 1596 of the CHD7 protein (p.Asp1596Gly). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and glycine.