rs1241595912
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong
The NM_000166.6(GJB1):c.491G>A(p.Arg164Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000183 in 1,093,603 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R164G) has been classified as Uncertain significance.
Frequency
Consequence
NM_000166.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GJB1 | NM_000166.6 | c.491G>A | p.Arg164Gln | missense_variant | 2/2 | ENST00000361726.7 | |
GJB1 | NM_001097642.3 | c.491G>A | p.Arg164Gln | missense_variant | 2/2 | ||
GJB1 | XM_011530907.3 | c.491G>A | p.Arg164Gln | missense_variant | 2/2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GJB1 | ENST00000361726.7 | c.491G>A | p.Arg164Gln | missense_variant | 2/2 | 1 | NM_000166.6 | P1 |
Frequencies
GnomAD3 genomes Cov.: 22
GnomAD3 exomes AF: 0.00000580 AC: 1AN: 172347Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 58611
GnomAD4 exome AF: 0.00000183 AC: 2AN: 1093603Hom.: 0 Cov.: 32 AF XY: 0.00000278 AC XY: 1AN XY: 359613
GnomAD4 genome Cov.: 22
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 13, 2021 | Published functional studies demonstrate a damaging effect, including reduced plasma membrane expression of GJB1 and GJ plaque formation combined with predominant cytoplasmic retention of GJB1, and impaired GJ permeability (Tsai et al., 2016); The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 10220155, 10737979, 12497641, 11571214, 23649551, 7580242, 9187667, 27098783, 18379723, 26454100, 9854984, 10923043, 17100997, 25025039, 20443038, 27544631, 15241803, 9361298, 14663027, 27844031, 15006706, 27025386, 27027447, 22243284, 31211173, 32022442, 31948496, 33726816) - |
Likely pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2023 | GJB1: PM1, PM2, PM5, PS4:Moderate, PS3:Supporting - |
Inborn genetic diseases Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 18, 2021 | The p.R164Q variant (also known as c.491G>A), located in coding exon 1 of the GJB1 gene, results from a G to A substitution at nucleotide position 491. The arginine at codon 164 is replaced by glutamine, an amino acid with highly similar properties. This variant has been reported in several individuals with Charcot-Marie-Tooth neuropathy X type 1 (CMTX1) (Ionasescu V et al. Neuromuscul Disord, 1995 Jul;5:297-9; Bort S et al. Hum Genet, 1997 Jun;99:746-54; Høyer H et al. Biomed Res Int, 2014 Jun;2014:210401; Michaelidou K et al. Mol Genet Genomic Med, 2020 04;8:e1141; Li LX et al. Oncotarget, 2016 May;7:27655-64; Wang R et al. Clin Chim Acta, 2015 Dec;451:263-70; Braathen GJ. Acta Neurol Scand Suppl, 2012;:iv-22; Yoshihara T et al. Hum Mutat, 2000 Aug;16:177-8; Karadima G et al. Clin Genet, 2011 Nov;80:497-9; Casasnovas C et al. Clin Genet, 2006 Dec;70:516-23; Choi BO et al. Hum Mutat, 2004 Aug;24:185-6; Dubourg O et al. Brain, 2001 Oct;124:1958-67; Huehne K et al. Hum Mutat, 2003 Jan;21:100; Tsai PC et al. Ann Clin Transl Neurol, 2016 11;3:854-865). Experimental studies have shown that this alteration causes mislocalization via cytoplasmic retention of GJB1 and significantly impairs Ca2+ signaling (Tsai PC et al. Ann Clin Transl Neurol, 2016 11;3:854-865). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |
Peripheral neuropathy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Kariminejad - Najmabadi Pathology & Genetics Center | Jul 10, 2021 | - - |
Charcot-Marie-Tooth Neuropathy X Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 31, 2023 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg164 amino acid residue in GJB1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7580242, 9187667, 15006706, 27025386, 27027447). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 164 of the GJB1 protein (p.Arg164Gln). Experimental studies have shown that this missense change affects GJB1 function (PMID: 27844031). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GJB1 protein function. ClinVar contains an entry for this variant (Variation ID: 543920). This missense change has been observed in individuals with Charcot-Marie-Tooth disease, type 1X (PMID: 9187667, 10923043, 11571214, 12497641, 15241803, 22243284, 23106488, 25025039, 26454100, 27027447). This variant is present in population databases (no rsID available, gnomAD 0.007%). - |
Charcot-Marie-Tooth disease X-linked dominant 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Nov 03, 2021 | - - |
Charcot-Marie-Tooth disease Uncertain:1
Uncertain significance, no assertion criteria provided | literature only | Inherited Neuropathy Consortium | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at