ClinVar

Description

The p.Leu236Pro variant in SLC26A4 has been reported in at least 15 individuals with either nonsyndromic hearing loss or Pendred syndrome who were homozygous or compound heterozygous, and it segregated in 4 affected family members from 2 fa milies (Busi 2012, Pryor 2005, Pourova 2010, Siem 2010, Van Hauwe 1998, LMM data ). One in vitro functional analysis study suggests the variant may impact normal intracellular trafficking of the protein (Rotman-Pikielny 2002). The p.Leu236Pr o variant has been identified in 0.1% (78/126638) of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs 80338848). Although this variant has been seen in the general population, its fr equency is low enough to be consistent with a recessive carrier frequency. In su mmary, this variant meets criteria to be classified as pathogenic for autosomal recessive hearing loss based on bi-allelic occurrences in multiple affected indi viduals, segregation studies, functional evidence, and low frequency in the gene ral population. ACMG/AMP criteria applied: PM3_VeryStrong, PP1_Moderate, PS3_Sup porting.