rs879254099
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000166.6(GJB1):c.643C>T(p.Arg215Trp) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R215Q) 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 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GJB1 | NM_000166.6 | c.643C>T | p.Arg215Trp | missense_variant | 2/2 | ENST00000361726.7 | |
GJB1 | NM_001097642.3 | c.643C>T | p.Arg215Trp | missense_variant | 2/2 | ||
GJB1 | XM_011530907.3 | c.643C>T | p.Arg215Trp | missense_variant | 2/2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GJB1 | ENST00000361726.7 | c.643C>T | p.Arg215Trp | 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 | Athena Diagnostics | Nov 18, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 17, 2020 | Published functional studies demonstrate a damaging effect as R215W prevents the formation of functional channels (Omori et al., 1996; Castro et al., 1999).; 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 has a deleterious effect on protein structure/function; Missense variants in nearby residues reported in the Human Gene Mutation Database (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 10234007, 11835375, 8816997, 8162049, 11571214, 32376792) - |
Charcot-Marie-Tooth disease X-linked dominant 1 Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 27, 2023 | Variant summary: GJB1 c.643C>T (p.Arg215Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 179956 control chromosomes. c.643C>T has been reported in the literature in multiple familial individuals affected with Charcot-Marie-Tooth disease X-linked dominant 1 (example, Fairweather_1994, Kovale_2021). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in about 20% of normal GJB1 levels, diminished gap junctional intercellular communication, and interfering WT allele of GJB1 through a dominant-negative mechanism in Hela cells (Omori_1996). The following publications have been ascertained in the context of this evaluation (PMID: 8162049, 34326750, 8816997). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Sep 25, 2023 | Criteria applied: PS4_MOD,PM5,PS3_SUP,PM2_SUP,PP3 - |
Charcot-Marie-Tooth Neuropathy X Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 19, 2023 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 215 of the GJB1 protein (p.Arg215Trp). 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 (CMT1X) (PMID: 8162049, 8698335, 9187667, 11437164, 11571214, 11835375, 16912585, 22464564, 25947624, 27098783). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 246098). 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 have shown that this missense change affects GJB1 function (PMID: 8816997, 10234007). For these reasons, this variant has been classified as Pathogenic. - |
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