rs111033211
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_004004.6(GJB2):c.109G>T(p.Val37Phe) variant causes a missense change. 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. V37I) has been classified as Likely pathogenic.
Frequency
Consequence
NM_004004.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome Cov.: 33
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
not provided Pathogenic:1
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. 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. 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. ClinVar contains an entry for this variant (Variation ID: 179256). This variant has not been observed in the literature in individuals with autosomal recessive GJB2-related conditions. This variant has been reported in individual(s) with clinical features of autosomal dominant GJB2-related conditions (Invitae); however, the role of the variant in this condition is currently unclear. This variant is not present in population databases (gnomAD no frequency). 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). -
Rare genetic deafness Pathogenic:1
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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at