ClinVar

Description

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)