ClinVar Genomic variation as it relates to human health

The p.Gly11Arg variant in GJB6 is one of the four pathogenic variant associated with hidrotic ectodermal dysplasia 2 (Clouston syndrome, HED2) and has been repo rted in >10 individuals with HED2 and segregated with disease in >30 affected fa mily members (Chen 2010, Common 2002, Fujimoto 2013, Lamartine 2000). In additi on, this variant has not been identified in large population studies. In summary , this variant meets our criteria to be classified as pathogenic (http://www.par tners.org/personalizedmedicine/LMM).

This variant has been previously reported as a heterozygous change in patients with Ectodermal dysplasia 2, Clouston type (PMID: 11017065, 12419304, 12788524, 15213106, 15769851, 23926005, 23981984, 24514865, 20301379, 26551294). Functional studies have demonstrated a deleterious effect on protein function (PMID: 12419304, 15213106, 15769851). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.00039% (1/250650) and thus is presumed to be rare. The c.31G>A (p.Gly11Arg) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.31G>A (p.Gly11Arg) variant is classified as Pathogenic.

The GJB6 c.31G>A variant is classified as a PATHOGENIC variant (PS4, PS3_supporting, PP1_moderate, PM2, PP3) The variant is a single nucleotide change in exon 5/5 of the GJB6 gene, which is predicted to change the amino acid glycine at position 11 in the protein to arginine. This is a recurrent pathogenic variant in the GJB6 gene. This variant has been previously reported in more than 10 unrelated individuals affected with Clouston syndrome and segregated with disease in affected family members in multiple families (PMID: 11017065, 20536673) (PS4) (PP1_moderate). Functional studies have demonstrated that this variant causes gain of hemichannel function, resulting in increased cells apoptosis and altered cell proliferation (PMID: 12419304, 15213106) (PS3_supporting). This variant is in dbSNP (rs104894415) but is rare in population databases (gnomAD: 1/152118, 0 homozygote) (PM2). This variant has been reported in ClinVar (Variation ID: 5544) and HGMD (Accession no: CM002605) as pathogenic/ disease causing. Computational predictions support a deleterious effect on the gene or gene product (PP3).

GJB6: PP1:Strong, PM2, PP4:Moderate, PS4:Moderate

ACMG classification criteria: PS1 strong, PS3 supporting, PS4 strong, PM2 supporting, PP1 strong, PP3 supporting

One of the most common, recurrent GJB6 pathogenic variants causing hidrotic ectodermal dysplasia, located in the cytoplasmic amino-terminus of the gap junction protein connexin 30; Functional in vitro studies have shown that G11R impairs trafficking of connexin 30 to the cell membrane, and forms gap junctions in keratinocyte cultures when co-expressed with other connexins (Di et al., 2005); other studies demonstrate gain of hemichannel function with leakage of ATP into the extracellular medium, increased cell apoptosis, and altered cell proliferation (Essenfelder et al. 2004; Lu Y at al., 2018); Same amino acid substitution caused by a different nucleotide change (c.31 G>C) has been reported as pathogenic in the published literature in association with hidrotic ectodermal dysplasia (Fujimoto et al., 2013; Kutkowska-Kazmierczak et al., 2015); 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: 12419304, 23926005, 24514865, 11017065, 27817781, 12788524, 27643550, 23219093, 20536673, 30043857, 30983611, 15213106, 36147510, 33074302, 23981984, 15769851, 25575739)

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 11 of the GJB6 protein (p.Gly11Arg). This variant is present in population databases (rs104894415, gnomAD 0.0009%). This missense change has been observed in individual(s) with ectodermal dysplasia (PMID: 11017065, 12788524, 23926005, 23981984, 24514865, 26551294, 27817781). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5544). 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 GJB6 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects GJB6 function (PMID: 12419304, 15213106, 15769851). For these reasons, this variant has been classified as Pathogenic.