Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2_SupportingPM5PP3_StrongPP5_Very_Strong
The NM_004004(GJB2):c.109G>T(p.Val37Phe) 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. V37A) has been classified as Likely pathogenic.
Verdict is Pathogenic. Variant got 17 ACMG points.
GnomAD3 genomesCov.: 33
Submissions by phenotype
Rare genetic deafness
|Likely pathogenic, criteria provided, single submitter||clinical testing||Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine||Oct 05, 2013||The Val37Phe variant in GJB2 has not been previously reported in individuals wit h hearing loss or in large population studies; however it was identified in tran s (on separate copies of the gene) with the 167delT pathogenic variant in this i ndividual by our laboratory. In addition, a known pathogenic variant at the same amino acid position (Val37Ile) has been reported in individuals with hearing lo ss that is typically mild to moderate (Snoeckx 2005, Huculak 2006, Pollak 2007). In summary, this variant is likely to be pathogenic because it is found in tran s with a pathogenic GJB2 variant in an affected individual and it alters the sam e amino acid residue affected by a known pathogenic GJB2 variant; however, addit ional studies are required to fully establish its clinical significance. -|
|Likely pathogenic, criteria provided, single submitter||clinical testing||Invitae||Aug 23, 2022||This sequence change replaces valine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 37 of the GJB2 protein (p.Val37Phe). 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: 179256). 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. This variant disrupts the p.Val37 amino acid residue in GJB2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12505163, 17935238, 24945352, 28489599). 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. -|
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