rs1378679640
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM5PP3_Strong
The NM_004004.6(GJB2):c.584T>C(p.Met195Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,662 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M195V) has been classified as Likely pathogenic.
Frequency
Consequence
NM_004004.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GJB2 | NM_004004.6 | c.584T>C | p.Met195Thr | missense_variant | 2/2 | ENST00000382848.5 | |
GJB2 | XM_011535049.3 | c.584T>C | p.Met195Thr | missense_variant | 2/2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GJB2 | ENST00000382848.5 | c.584T>C | p.Met195Thr | missense_variant | 2/2 | 1 | NM_004004.6 | P1 | |
GJB2 | ENST00000382844.2 | c.584T>C | p.Met195Thr | missense_variant | 1/1 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251352Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135864
GnomAD4 exome AF: 0.00000684 AC: 10AN: 1461662Hom.: 0 Cov.: 32 AF XY: 0.00000963 AC XY: 7AN XY: 727142
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
not provided Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Dec 26, 2017 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 17, 2023 | This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 195 of the GJB2 protein (p.Met195Thr). This variant is present in population databases (no rsID available, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of autosomal recessive deafness (PMID: 19235794, 20233142). ClinVar contains an entry for this variant (Variation ID: 438620). 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 GJB2 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects GJB2 function (PMID: 23967136). This variant disrupts the p.Met195 amino acid residue in GJB2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20497192, 24013081, 30146550, 33597575). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 13, 2023 | Variant summary: GJB2 c.584T>C (p.Met195Thr) results in a non-conservative amino acid change located in the Gap junction protein, cysteine-rich domain (IPR019570) of the encoded protein sequence. This alters a highly conserved residue in which other missense variants have been found in association with hearing loss (HGMD). Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251352 control chromosomes (gnomAD). c.584T>C has been reported in the literature in individuals affected with Non-Syndromic Hearing Loss without strong evidence of causality (Lee_2009, Chinetti_2010). These reports do not provide unequivocal conclusions about association of the variant with Non-Syndromic Hearing Loss. At least one publication reports experimental evidence evaluating an impact on protein function, funding no impact on gap junction formation or stability but substantially reduced function (Ambrosi_2013). The following publications have been ascertained in the context of this evaluation (PMID: 19235794, 23967136, 20233142). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as uncertain significance (n=2) or likely benign (n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. - |
Autosomal recessive nonsyndromic hearing loss 1A Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia | May 09, 2017 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at