chrX-71223784-C-T
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000166.6(GJB1):c.77C>T(p.Ser26Leu) 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S26W) has been classified as Pathogenic.
Frequency
Consequence
NM_000166.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GJB1 | NM_000166.6 | c.77C>T | p.Ser26Leu | missense_variant | 2/2 | ENST00000361726.7 | |
GJB1 | NM_001097642.3 | c.77C>T | p.Ser26Leu | missense_variant | 2/2 | ||
GJB1 | XM_011530907.3 | c.77C>T | p.Ser26Leu | missense_variant | 2/2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GJB1 | ENST00000361726.7 | c.77C>T | p.Ser26Leu | missense_variant | 2/2 | 1 | NM_000166.6 | P1 |
Frequencies
GnomAD3 genomes Cov.: 22
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 22
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Jan 29, 2019 | Not found in the total gnomAD dataset, and the data is high quality (0/204891 chr). Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Damaging to protein function(s) relevant to disease mechanism. Moderate co-segregation with disease in affected and unaffected individuals, but from a single family. One de novo case without parental identity confirmed. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 26, 2018 | The S26L missense variant in the GJB1 gene has been reported previously in association with CMTX1 (Oh et al., 1997; Nelis et al., 1997; Sun et al., 2016). Functional analysis shows that S26L alters the structure and permeability of the membrane (Oh et al., 1997). The S26L variant is not observed in large population cohorts (Lek et al., 2016). The S26L variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Additionally, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Furthermore, missense variants in nearby residues have been reported in the Human Gene Mutation Database in individuals with CMTX1 (Stenson et al., 2014). Therefore, S26L is interpreted to be a pathogenic variant. - |
Charcot-Marie-Tooth disease X-linked dominant 1 Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jan 12, 2021 | The GJB1 c.77C>T; p.Ser26Leu variant (rs587777876) is reported in the literature in multiple individuals affected with X-linked Charcot-Marie-Tooth disease (selected references: Yoshimura 1996, Hsu 2019, and Niu 2020). In vitro functional analyses demonstrate that the p.Ser26Leu alters the channels junctional permeability by reducing the pore size (Tsai 2016). This variant is also absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. Based on available information, this variant is considered to be pathogenic. - |
Pathogenic, no assertion criteria provided | literature only | Northcott Neuroscience Laboratory, ANZAC Research Institute | - | - - |
Charcot-Marie-Tooth Neuropathy X Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 13, 2023 | This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 26 of the GJB1 protein (p.Ser26Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Charcot-Marie-Tooth disease, type 1X (PMID: 8990008, 9354338, 11271367, 21291455, 25429913, 25802885, 27862672). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 155726). 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: 9354338, 16442804, 27844031). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at