Submissions for variant NM_000166.6(GJB1):c.113T>G (p.Val38Gly)

dbSNP: rs863224612

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000199414	SCV000254267	uncertain significance	Charcot-Marie-Tooth Neuropathy X	2022-11-08	criteria provided, single submitter	clinical testing	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 variant disrupts the p.Val38 amino acid residue in GJB1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7833935, 9354338, 9888385, 10400511, 10521546, 12111842, 12457340, 12460545). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 expected to disrupt GJB1 protein function. ClinVar contains an entry for this variant (Variation ID: 216292). This missense change has been observed in individual(s) with Charcot-Marie-Tooth disease (Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 38 of the GJB1 protein (p.Val38Gly).
GeneDx	RCV000235965	SCV000293165	likely pathogenic	not provided	2015-09-17	criteria provided, single submitter	clinical testing	The V38G variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. However, different amino acid substitutions at this same position (V38M/A) and many missense variants in nearby residues (I33N, M34V/K/T, V35M, L36P, V37L/M, A39P/G/V, A40T/V) have been reported in the Human Gene Mutation Database in association with CMT neuropathy (Stenson et al., 2014), supporting the functional importance of this region of the protein. V38G was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In silico analysis predicts this variant is probably damaging to the protein structure/function. However, the V38G variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties, and this substitution occurs at a position where amino acids with similar properties to Valine are tolerated across species. Therefore, this variant is a strong candidate for a pathogenic variant, however the possibility that it is a benign variant cannot be excluded.