Submissions for variant NM_004004.6(GJB2):c.110T>C (p.Val37Ala)

gnomAD frequency: 0.00014  dbSNP: rs141774369

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Hearing Loss Variant Curation Expert Panel	RCV001252676	SCV001428435	likely pathogenic	Nonsyndromic genetic hearing loss	2024-04-22	reviewed by expert panel	curation	The c.1101T>C variant in GJB2 is a missense variant predicted to cause substitution of valine by alanine at amino acid 37 (p.Val37Ala). The highest population filtering allele frequency in gnomAD v4 is 0.03% (25/74924 alleles) in the African American population (PM2_Supporting, BA1, and BS1 not met). This variant has been identified in 11 heterozygous individuals who did not harbor a second variant in GJB2 (PMID 21287563, PMID 17666888, PMID 15365987,GeneDx Internal Data, Invitae Internal Data), but has also been detected in 1 patient with hearing loss in trans with a pathogenic variant (1 point, PM3; Partners LMM internal data SCV000967620.2, GeneDx Internal Data, Invitae Internal Data). The REVEL computational prediction analysis tool produced a score of 0.675, which rounded up to 0.7 is above the threshold necessary to apply PP3 (PP3). Two different pathogenic missense variants (p.Val37Ile and p.Val37Phe) have been previously identified at this codon of GJB2 which may indicate that this residue is critical to the function of the protein (PM5_Strong, p.Val37Ile ClinVar Variation ID 17023, PMID 31160754; p.Val37Phe ClinVar Variation ID:179256 PMID: 37108562). In summary, this variant meets criteria to be classified as likely pathogenic for autosomal recessive nonsyndromic hearing loss based on the ACMG/AMP criteria applied as specified by the ClinGen Hearing Loss VCEP: PM3, PM5_Strong, PP3. (Hearing Loss VCEP specifications version 2; 4/22/2024)
GeneDx	RCV000520583	SCV000617689	uncertain significance	not provided	2024-04-18	criteria provided, single submitter	clinical testing	Observed heterozygous with no other GJB2 variants in patients with hearing loss in published literature (PMID: 15365987, 17666888, 21287563); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25388846, 21287563, 25087612, 17666888, 27466889, 15365987, 36048236)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000855645	SCV000698224	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2021-02-24	criteria provided, single submitter	clinical testing	Variant summary: GJB2 c.110T>C (p.Val37Ala) results in a non-conservative amino acid change located in the Connexin, N-terminal domain (IPR013092) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.6e-05 in 250894 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in GJB2 causing Autosomal Recessive Non-Syndromic Hearing Loss (7.6e-05 vs 0.025), allowing no conclusion about variant significance. c110T>C has been reported in the literature in individuals affected with congenital deafness (Azaiez_2004), non-syndromic sensorineural hearing loss (Lipan_2011), moderate hearing loss (Putcha_2007) and sensorineural hearing loss (Gruber_2016). A second variant in the GJB2 gene was not identified in the individuals reported in these studies, however the variant was reported to co-occur with a GJB6 variant (c.631T>G, p.C211G) of unknown pathogenicity in one patient (Putcha_2007). In addition, one Clinvar submitter reports that this variant has been detected in trans with a second pathogenic GJB2 variant in an individual with hearing loss tested at their facility. These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories cited the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000826112	SCV000967620	likely pathogenic	Rare genetic deafness	2019-03-06	criteria provided, single submitter	clinical testing	The p.Val37Ala variant in GJB2 has been previously reported in several individuals with hearing loss in whom a second GJB2 variant was not identified. However, this variant has also been identified by our laboratory in one individual with hearing loss who carried a second pathogenic GJB2 variant. This variant has been identified in 0.036% (13/35428) of Latino chromosomes and in 0.36% (9/24968) of African by gnomAD (http://gnomad.broadinstitute.org), which are low enough to be consistent with recessive carrier frequencies. Computational prediction tools and conservation analysis suggest an impact to the protein. Furthermore, a pathogenic (p.Val37Ile) and likely pathogenic (p.Val37Phe) at the same amino acid residue have been previously reported in individuals with hearing loss. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive hearing loss. ACMG/AMP criteria applied: PM3, PM5, PM2_Supporting, PP3.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000520583	SCV004309301	likely pathogenic	not provided	2024-01-20	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 37 of the GJB2 protein (p.Val37Ala). This variant is present in population databases (rs141774369, gnomAD 0.04%). This missense change has been observed in individual(s) with autosomal recessive deafness (PMID: 15365987, 17666888). ClinVar contains an entry for this variant (Variation ID: 449490). 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.Val37 amino acid residue in GJB2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15365987, 17666888). 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.
Natera, Inc.	RCV000855645	SCV002086066	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2020-03-09	no assertion criteria provided	clinical testing