ClinVar

Description

The SLC26A4 c.2171A>G (p.Asp724Gly) missense variant has been reported in at least three studies and is found in a total of four probands, including three probands in a compound heterozygous state and one proband in a heterozygous state (Prasad et al. 2004; Pera et al. 2008; Ladsous et al. 2014). Of the three compound heterozygous probands; two probands were clinically diagnosed with Pendred syndrome and one proband was noted to have non-syndromic enlarged vestibular aqueduct. The heterozygous proband was described to have non-syndromic hearing loss, although an alternate etiology was suspected to be causative, this phenotype and thus this proband was considered a coincidental carrier of the p.Asp724Gly variant (Pera et al. 2008). The p.Asp724Gly variant was reported in two of 648 controls alleles and is reported at a frequency of 0.000032 in the European (non-Finnish) population of the Genome Aggregation Database. The Asp724 residue is highly conserved. The p.Asp724Gly variant protein was expressed in HEK-293 phoenix cells and had no detectable iodide transport when analyzed with fluorometry, indicating complete inactivation in comparison to wildtype (Pera et al. 2008). Based on the evidence, the p.Asp724Gly variant is classified as likely pathogenic for SLC26A4-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.