rs879253909
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong
The NM_000166.6(GJB1):c.541G>A(p.Val181Met) variant causes a missense change involving the alteration of a non-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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V181E) has been classified as Likely pathogenic.
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.541G>A | p.Val181Met | missense_variant | 2/2 | ENST00000361726.7 | |
GJB1 | NM_001097642.3 | c.541G>A | p.Val181Met | missense_variant | 2/2 | ||
GJB1 | XM_011530907.3 | c.541G>A | p.Val181Met | missense_variant | 2/2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GJB1 | ENST00000361726.7 | c.541G>A | p.Val181Met | missense_variant | 2/2 | 1 | NM_000166.6 | P1 |
Frequencies
GnomAD3 genomes Cov.: 21
GnomAD4 exome Cov.: 32
GnomAD4 genome Cov.: 21
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 05, 2020 | Not observed in large population cohorts (Lek et al., 2016); Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 9361298, 17100997, 31372974, 19259128, 21692908, 25947624, 28071741, 32903794, 33136338) - |
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Jun 28, 2021 | This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause disease. Computational tools predict that this variant is damaging. The variant is located in a region that is considered important for protein function and/or structure. - |
Charcot-Marie-Tooth Neuropathy X Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 17, 2023 | This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 181 of the GJB1 protein (p.Val181Met). 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: 9361298, 17100997, 19259128, 21692908, 25947624). ClinVar contains an entry for this variant (Variation ID: 245705). 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%. This variant disrupts the p.Val181 amino acid residue in GJB1. Other variant(s) that disrupt this residue have been observed in individuals with GJB1-related conditions (PMID: 14627639, 18380028), 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 X-linked dominant 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | May 24, 2022 | The GJB1 c.541G>A variant is classified as a LIKLEY PATHOGENIC VARIANT (PM2, PP2, PP3, PS4_S, PM1_S, PM5_S) This variant is a single nucleotide change in exon 2/2 of the GJB1 gene, which is predicted to change the amino acid valine at position 181 in the protein to methionine. The variant is located in a mutational hot spot (PM1_S). Missense variant in the GJB1 gene are a common mechanism of disease, and has a low rate of benign missense variation (PP2). This variant is at an amino acid residue where several different missense changes determined to be pathogenic have been reported previously (PM5_S). The variant has been reported in dbSNP (rs879253909) but is absent from population databases (PM2). The variant has been repored in ClinVar (VariationID: #245705) and HGMD (Accession: CM973178) as pathogenic/ disease causing variant (PS4_S). Computational predictions support a deleterious effect on the gene or gene product (PP3). - |
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