ClinVar

Description

The SLC26A4 c.-103T>C 5' UTR variant has been reported in at least four studies in which it was found in a total of 14 individuals with clinical features of Pendred syndrome or isolated hearing loss/impairment or nonsyndromic enlarged vestibular aqueduct. Among these individuals, the variant was identified in a compound heterozygous state in one individual, in conjunction with a second missense variant in one individual (phase unknown), and in a heterozygous state in 12 individuals (Yang et al. 2007; Choi et al. 2009; Landa et al. 2013; Tang et al. 2015). Although SLC26A4-related disorders are inherited in an autosomal recessive manner, it is not uncommon to detect a single disease-causing variant in patients due to testing limitations and biological complexities. Frequency information for the c.-103T>C variant is not available from the 1000 Genomes Project, the Exome Sequencing Project or the Exome Aggregation Consortium; however, the variant was absent from 452 control chromosomes (Yang et al. 2007; Choi et al. 2009). A luciferase promotor-reporter expression assay showed the variant reduces FOXI1 binding affinity and abolishes FOXI1-mediated transcriptional activation of SLC26A4 (Yang et al. 2007). Evidence for this variant is limited, therefore, the c.-103T>C variant is classified as a variant of unknown significance but suspicious for pathogenicity for SLC26A4-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.