ClinVar Miner

Submissions for variant NM_004004.6(GJB2):c.187G>T (p.Val63Leu)

dbSNP: rs370696868
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV001857901 SCV000613507 likely pathogenic not provided 2023-07-19 criteria provided, single submitter clinical testing The frequency of this variant in the general population is consistent with pathogenicity. (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)) This variant is statistically significantly enriched in affected patients as compared to ethnically matched controls. Computational tools predict that this variant is damaging.
Counsyl RCV000668102 SCV000792653 uncertain significance Autosomal recessive nonsyndromic hearing loss 1A 2017-07-05 criteria provided, single submitter clinical testing
Invitae RCV001857901 SCV002309067 pathogenic not provided 2023-12-10 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 63 of the GJB2 protein (p.Val63Leu). This variant is present in population databases (rs370696868, gnomAD 0.02%). This missense change has been observed in individual(s) with GJB2-related conditions (PMID: 12792423, 25266519, 34403091; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 447443). 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%. This variant disrupts the p.Val63 amino acid residue in GJB2. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
New York Genome Center RCV003335444 SCV004046508 uncertain significance Autosomal dominant nonsyndromic hearing loss 3A 2023-05-08 criteria provided, single submitter clinical testing The inherited heterozygous c.187G>T p.(Val63Leu) variant identified in the GJB2 gene has previously been reported as heterozygous in multiple individuals with non‐syndromic hearing loss [PMID: 21557232, 26252218, 26043044, 19366456, 24612839, 25266519, others] and as compound heterozygous in at least two families with recessively inherited hearing loss [PMID: 19707039, 24507663]. This variant has been deposited in ClinVar [ClinVar ID:447443] as Variant of Uncertain Significance (2 submissions) and Likely Pathogenic (1 submission), and was classified as a Variant of Uncertain by a recent study[PMID: 36048236]. In population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8), the c.187G>T variant is observed at ~0.0027% minor allele frequency across populations (with 0 homozygotes), including ~0.03% minor allele frequency in East Asian sub-population which is higher than the expected maximum allele frequency for a pathogenic variant in the GJB2-related dominant hearing loss [https://cspec.genome.network/cspec/ui/svi/doc/GN005]. The c.187G>T variant in GJB2is located in exon 2 of this 2-exon gene and is predicted to replace an evolutionarily conserved valine amino acid with leucine at position 63 of the encoded protein.In silico predictions are in favor of damaging effect for p.(Val63Leu) [REVEL = 0.929]; however, there are no functional studies to support or refute these predictions. Due to the lack of compelling evidence for its pathogenicity, this inherited heterozygous c.187G>T p.(Val63Leu) variant identified in GJB2 is classified as a Variant of Uncertain Significance for GJB2-related autosomal dominant hearing loss.
Natera, Inc. RCV000668102 SCV001453349 uncertain significance Autosomal recessive nonsyndromic hearing loss 1A 2020-09-16 no assertion criteria provided clinical testing

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