Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2_SupportingPM5PP3_StrongPP5_Very_Strong
The NM_004004(GJB2):c.101T>G(p.Met34Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD Genomes 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. M34T) has been classified as Pathogenic.
Verdict is Pathogenic. Variant got 17 ACMG points.
GnomAD3 genomesCov.: 33
Submissions by phenotype
|Likely pathogenic, criteria provided, single submitter||clinical testing||GeneDx||Oct 20, 2021||Reported in a patient with hearing loss in published literature (Putcha et al., 2007); however, clinical and molecular data were limited; Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Splice predictors and evolutionary conservation suggest this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 25388846, 17666888, 31589614) -|
|Likely pathogenic, criteria provided, single submitter||clinical testing||Invitae||Aug 15, 2022||This sequence change replaces methionine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 34 of the GJB2 protein (p.Met34Arg). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with GJB2-related conditions. ClinVar contains an entry for this variant (Variation ID: 44722). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant disrupts the p.Met34 amino acid residue in GJB2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16077952, 22668073, 26117665; Invitae). 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. -|
Rare genetic deafness
|Likely pathogenic, no assertion criteria provided||clinical testing||Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine||Feb 19, 2009||- -|
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