rs879254097
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5
The NM_000166.6(GJB1):c.239A>G(p.Gln80Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000166.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
GJB1 | NM_000166.6 | c.239A>G | p.Gln80Arg | missense_variant | Exon 2 of 2 | ENST00000361726.7 | NP_000157.1 | |
GJB1 | NM_001097642.3 | c.239A>G | p.Gln80Arg | missense_variant | Exon 2 of 2 | NP_001091111.1 | ||
GJB1 | XM_011530907.3 | c.239A>G | p.Gln80Arg | missense_variant | Exon 2 of 2 | XP_011529209.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 23
GnomAD4 exome Cov.: 32
GnomAD4 genome Cov.: 23
ClinVar
Submissions by phenotype
not provided Pathogenic:2
This variant has not been reported in large, multi-ethnic general populations. (http://gnomad.broadinstitute.org) In some published literature, this variant is referred to as c.301A>G, (p.Gln80Arg). Assessment of experimental evidence regarding the effect of this variant on protein function is inconclusive (PMID: 15006706). This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. This variant occurs as the most likely explanation for disease in a significant number of internal cases, suggesting this variant is associated with disease. -
Functional studies show that the Q80R variant is capable of forming a functional gap junction protein, and the authors conclude that further functional studies are necessary to elucidate the effect, if any, of the Q80R variant (Wang et al., 2004); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); Not observed at significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 30042657, 25449862, 15006706, 9361298, 28211240, 17353473, 8737658, 10873293, 10737979, 7580242) -
Charcot-Marie-Tooth Neuropathy X Pathogenic:1
This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 80 of the GJB1 protein (p.Gln80Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Charcot-Marie-Tooth disease (PMID: 7580242, 10737979, 17353473; Invitae). ClinVar contains an entry for this variant (Variation ID: 246096). 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 with a positive predictive value of 80%. Experimental studies have shown that this missense change does not substantially affect GJB1 function (PMID: 15006706). This variant disrupts the p.Gln80 amino acid residue in GJB1. Other variant(s) that disrupt this residue have been observed in individuals with GJB1-related conditions (PMID: 22464564, 28286897), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -
Charcot-Marie-Tooth disease Uncertain:1
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Inborn genetic diseases Uncertain:1
The p.Q80R variant (also known as c.239A>G), located in coding exon 1 of the GJB1 gene, results from an A to G substitution at nucleotide position 239. The glutamine at codon 80 is replaced by arginine, an amino acid with highly similar properties. This alteration has been detected in individuals with features consistent with Charcot-Marie-Tooth neuropathy X type 1 (CMTX1); however, clinical details were limited (Mersiyanova IV et al. Hum Mutat, 2000;15:340-7; Ionasescu V et al. Am J Med Genet, 1996 Jun;63:486-91). Functional studies in vitro have shown that Q80R retains its ability to form homotypic junctional channels, similar to wild-type cells (Wang HL et al. Neurobiol Dis, 2004 Mar;15:361-70). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at