ClinVar Genomic variation as it relates to human health

The R15W mutation has been previously reported in association with Charcot-Marie-Tooth neuropathy (Wicklein et al., 1997), and functional studies show that the R15W mutation significantly alters the channel function (Abrams et al., 2001). Additionally, a different amino acid substitution at the same position (R15Q) and other missense mutations in nearby residues (V13L/M, N14S, H16L/P/Q) have been reported in the Human Gene Mutation Database in association with Charcot-Marie-Tooth neuropathy (Stenson et al., 2014), supporting the functional importance of this region of the protein. R15W 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.

This variant has been identified in multiple unrelated individuals with clinical features associated with this gene and segregates with disease in at least one family. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause disease. In some published literature, this variant is referred to as c.105C>T. Assessment of experimental evidence suggests this variant results in abnormal protein function. The variant significantly reduced channel conductance (PMID: 11325342).

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Charcot-Marie-Tooth neuropathy, X-linked dominant, 1 (MIM#1302800) (PMID 30042657). (I) 0110 - This gene is associated with X-linked dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance with some females remaining asymptomatic (GeneReviews).(I) 0115 - Variants in this gene are known to have variable expressivity (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan. (I) 0253 - This variant is hemizygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated connexin domain (DECIPHER). (I) 0703 - Other missense variants comparable to the one identified in this case have moderate previous evidence for pathogenicity. The GJB1 c.44G>A; p.(Arg15Gln) and c.44G>C; p.(Arg15Pro) variants have been previously reported in multiple individuals with Charcot-Marie-Tooth neuropathy (ClinVar; LOVD). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in multiple unrelated individuals with Charcot-Marie-Tooth neuropathy (ClinVar; LOVD). (SP) 1102 - Strong phenotype match for this individual. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 15 of the GJB1 protein (p.Arg15Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with CMT (PMID: 9099841, 9328258, 9600589, 10521546, 11835375, 21149811). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 21084). 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. Experimental studies have shown that this missense change affects GJB1 function (PMID: 11325342, 22771394). For these reasons, this variant has been classified as Pathogenic.