Submissions for variant NM_000166.6(GJB1):c.532G>A (p.Asp178Asn)

dbSNP: rs1555937223

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000537790	SCV000658915	uncertain significance	Charcot-Marie-Tooth Neuropathy X	2023-09-14	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 178 of the GJB1 protein (p.Asp178Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of Charcot-Marie-Tooth disease (Invitae). ClinVar contains an entry for this variant (Variation ID: 477600). 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 GJB1 protein function. Experimental studies have shown that this missense change affects GJB1 function (PMID: 14663144). This variant disrupts the p.Asp178 amino acid residue in GJB1. Other variant(s) that disrupt this residue have been observed in individuals with GJB1-related conditions (PMID: 20193560), which suggests that this may be a clinically significant amino acid residue. 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.
CeGaT Center for Human Genetics Tuebingen	RCV001531787	SCV001747068	pathogenic	not provided	2021-06-01	criteria provided, single submitter	clinical testing