Submissions for variant NM_001110219.3(GJB6):c.212T>C (p.Val71Ala)

gnomAD frequency: 0.00032  dbSNP: rs200172266

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001110826	SCV001268308	uncertain significance	Hidrotic ectodermal dysplasia syndrome	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
GeneDx	RCV001563386	SCV001786317	likely benign	not provided	2021-04-23	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function
Labcorp Genetics (formerly Invitae), Labcorp	RCV001862881	SCV002142956	uncertain significance	Autosomal recessive nonsyndromic hearing loss 1A; Autosomal recessive nonsyndromic hearing loss 1B; Autosomal dominant nonsyndromic hearing loss 3B; Hidrotic ectodermal dysplasia syndrome	2024-12-24	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 71 of the GJB6 protein (p.Val71Ala). This variant is present in population databases (rs200172266, gnomAD 0.08%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with GJB6-related conditions. ClinVar contains an entry for this variant (Variation ID: 881662). 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 GJB6 protein function with a positive predictive value of 80%. 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.
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001563386	SCV001959494	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001563386	SCV001970178	uncertain significance	not provided		no assertion criteria provided	clinical testing