ClinVar

Description

The c.1963A>G variant in SLC26A4 is a missense variant predicted to cause substitution of isoleucine by valine at amino acid 655 (p.Ile655Val). The highest population minor allele frequency in gnomAD v2.1.1 is .005% (2/34558) in the Latino population, which is lower than the ClinGen Hearing Loss VCEP threshold (<0.007) for PM2_Supporting, meeting this criterion (PM2_Supporting). This variant has been detected in 2 probands with hearing loss and enlarged vestibular aqueducts (PP4; Laboratory for Molecular Medicine internal data, PMID: 26894580). In one of those probands, a pathogenic variant (VCV000004818.5) was observed in trans, and the variant was observed in the homozygous state in the other proband (PM3; Laboratory for Molecular Medicine internal data, PMID: 26894580).The compound heterozygous individual had an affected sibling in whom both variants segregated (PP1; Laboratory for Molecular Medicine internal data). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. This variant was re-reviewed on 8.22.23 and because no additional evidence is available, professional judgment was used to retain this variant as likely pathogenic for autosomal recessive Pendred syndrome. In summary, this variant is classified as likely pathogenic for autosomal recessive Pendred syndrome. ACMG/AMP Criteria applied as specified by the Hearing Loss Expert Panel 8/22/2023 (PM2_Supporting, PP4, PM3, PP1)