ClinVar Genomic variation as it relates to human health

This variant has been previously reported as heterozygous or hemizygous change in patients with Charcot-Marie-Tooth disease (PMID: 7580242, 12542510). The variant has been reported as pathogenic by two clinical laboratories in the ClinVar database (SCV000544775, SCV000613500). In vitro studies on the functional impact of the p.Arg22Gln variant are conflicting (PMID: 11393532, 15006706). It is absent from the ExAC and gnomAD population databases and thus is presumed to be rare. The c.65G>A (p.Arg22Gln) 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.65G>A (p.Arg22Gln) variant is classified as likely pathogenic.

PP1, PP3, PM1, PM2, PM5, PM6, PS4

This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. This variant associates with disease in multiple families, and has been found de novo in at least one case (PMID: 9272161). This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). Computational tools predict that this variant is damaging.

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 22 of the GJB1 protein (p.Arg22Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Charcot-Marie-Tooth disease (CMT) (PMID: 7580242, 8737658, 9272161, 9600589, 9633821, 10521546, 11835375, 12542510, 17353473, 26454100). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 406228). 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 with a negative predictive value of 80%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on GJB1 function (PMID: 11393532, 15006706). For these reasons, this variant has been classified as Pathogenic.

This sequence change in GJB1 is predicted to replace arginine with glutamine at codon 22, p.(Arg22Gln). The arginine residue is highly conserved (100 vertebrates, UCSC), and is located in a transmembrane region. There is a small physicochemical difference between arginine and glutamine. This variant is absent from gnomAD v2.1 and v3.1. This variant has been reported in at least 11 probands with Charcot-Marie-Tooth neuropathy type 1/1X (CMT1/CMT1X; PMID: 7580242, 9272161, 26454100, 29998508, 33314704). The variant has been reported to segregate with neuropathy in at least four families, including affected females with less severe disease (PMID: 7580242, 9272161, 18358413). This variant has been identified as a de novo occurrence with confirmed parental relationships in one individual with CMT1 (PMID: 9272161). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (5/6 algorithms). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as PATHOGENIC. Following criteria are met: PP1_Strong, PS2_Moderate, PS4_Moderate, PM2_Supporting, PP3.

The p.R22Q variant (also known as c.65G>A), located in coding exon 1 of the GJB1 gene, results from a G to A substitution at nucleotide position 65. The arginine at codon 22 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported to cosegregate with disease in multiple unrelated patients and families with CMTX (Boerkoel CF et al. Ann. Neurol., 2002 Feb;51:190-201; Senderek J et al. J. Neurol. Sci., 1999 Aug;167:90-101; Silander K et al. Hum. Genet., 1997 Sep;100:391-7; Takashima H et al. Acta Neurol. Scand., 2003 Jan;107:31-7). De novo occurrence has also been reported in an affected patient (Silander K et al. Hum. Genet., 1997 Sep;100:391-7). The functional mechanism of this alteration remains to be elucidated and experimental studies performed in different cell lines have shown conflicting results as protein localization and channel formation were aberrant in PC12 cells (Matsuyama W et al. J. Hum. Genet., 2001;46:307-13) but preserved in N2A cells (Wang HL et al. Neurobiol. Dis., 2004 Mar;15:361-70). In addition to the clinical data presented in the literature, this alteration is predicted to be deleterious by in silico analysis, and is not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.