Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV001731332 | SCV001983846 | pathogenic | not provided | 2023-12-15 | criteria provided, single submitter | clinical testing | Reported in a patient with hearing loss in published literature; however, clinical and molecular data were limited (PMID: 17666888); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis suggests 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, 31589614, 36672810, 31160754, 17666888, 36048236) |
| Labcorp Genetics |
RCV001731332 | SCV003442021 | likely pathogenic | not provided | 2024-04-06 | criteria provided, single submitter | clinical testing | 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 with a positive predictive value of 95%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus 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. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV005055542 | SCV005726911 | uncertain significance | not specified | 2024-11-08 | criteria provided, single submitter | clinical testing | Variant summary: GJB2 c.101T>G (p.Met34Arg) 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. Several computational tools predict a significant impact on normal splicing: Four predict the variant creates a cryptic 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 250736 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.101T>G has been reported in the literature in an individual affected with Non-Syndromic Hearing Loss (Putcha_2007). These data do not allow any conclusion about variant significance. A different variant affecting the same codon has been classified as pathogenic by our lab (c.101T>C, p.Met34Thr), supporting the critical relevance of codon 34 to GJB2 protein function. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 17666888). ClinVar contains an entry for this variant (Variation ID: 44722). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. |
| Laboratory for Molecular Medicine, |
RCV000037811 | SCV000061473 | likely pathogenic | Rare genetic deafness | 2009-02-19 | no assertion criteria provided | clinical testing |