ClinVar

Description

Variant summary: SLC26A4 c.1231G>A (p.Ala411Thr) results in a non-conservative amino acid change located in the SLC26A/SulP transporter domain (IPR011547) of the encoded protein sequence. This amino acid is locaded in a mutational hot spot in which other pathogenic/likely pathogenic variants are found, including one affecting the same nucleotide (c.1231G>C, p.Ala411Pro) and p.Ala411Thr is predicted by computational modeling to alter the protein structure (Bassot_2017, Rapp_2017). Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250828 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1231G>A has been reported in the literature in an individual affected with Hearing loss with dilation of vestibular aqueduct (Courtmans_2007), and this individual was reported as compound heterozygous, carrying another pathogenic variant. These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and both classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.