ClinVar

Description

The SLC26A4 c.2168A>G (p.His723Arg) missense variant is a common founder variant in both the Japanese and Korean populations (Park et al. 2003). Across a selection of the available literature, it has been identified in a homozygous state in 26 patients, in a compound heterozygous state in 67 patients, and in a heterozygous state in 19 patients, including those with Pendred syndrome and autosomal recessive nonsyndromic hearing loss with enlarged vestibular aqueduct (Tsukamoto et al. 2003; Park et al. 2005; Cho et al. 2006; Kim et al. 2009; Reyes et al. 2009; Miyagawa et al. 2014; Lu et al. 2015; Tsukada et al. 2015). Family studies have demonstrated inheritance of the variant from unaffected heterozygous parents. The p.His723Arg variant was identified in a heterozygous state in three of 1024 Asian control alleles (Park et al. 2003; Yuan et al. 2012; Miyagawa et al. 2014) and is reported at a frequency of 0.00174 in the East Asian population of the Exome Aggregation Consortium. Functional studies in HEK 293 and HeLa cells showed the variant causes the protein to be retained in the endoplasmic reticulum rather than localized to the cell membrane and significantly reduces chloride bicarbonate ion exchange function, consistent with the proposed disease mechanism. The defects were rescued by incubation at low temperature, suggesting they may be due to protein misfolding (Yoon et al. 2008). Based on the collective evidence, the p.His723Arg variant is classified as pathogenic for SLC26A4-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.