ClinVar Miner

Submissions for variant NM_000441.2(SLC26A4):c.1708G>A (p.Val570Ile) (rs397516421)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000036456 SCV000060111 uncertain significance not specified 2014-09-12 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The p.Val570Ile variant in SLC26A4 has been identified by our laboratory in two Ashkenazi Jewis h individuals with hearing loss and EVA who also carried a second SLC26A4 varian t of uncertain clinical significance and one individual with hearing loss and Mo ndini dysplasia who did not carry a second pathogenic variant in the SLC26A4 gen e. Moreover, this variant has been identified in one other proband as reported o n the MORL website (www.healthcare.uiowa.edu/labs/pendredandbor/slcMutations.htm ), but was absent from large population studies. The valine (Val) residue at pos ition 570 is highly conserved across species. In addition, the G nucleotide at p osition 1708 is located within the 3? splice junction consensus sequence and the refore could impact splicing (in silico programs suggest a modest divergence fro m consensus). In summary, the clinical significance of the p.Val570Ile variant i s uncertain; however the available data suggest that it is more likely to be pat hogenic.
GeneDx RCV000497745 SCV000589698 likely pathogenic not provided 2017-10-20 criteria provided, single submitter clinical testing The V570I variant in the SLC26A4 gene has been reported previously in a database of pathogenic variants associated with hearing loss (MORL website: www.healthcare.uiowa.edu/labs/pendredandbor/slcMutations.htm). In addition, V570I has been reported in the ClinVar database as a variant of uncertain significance (Landrum et al., 2014). The V570I variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The V570I variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position in the cytoplasmic STAS domain that is conserved across species (Sharma et al., 2011). In silico analysis predicts V570I is probably damaging to the protein structure/function. As an alternate mechanism, some in silico algorithms predict that c.1708 G>A (aka p.V570I) damages the natural splice acceptor site in intron 15. However, in the absence of RNA/functional studies, the actual effect of c.1708 G>A in this individual is unknown. Missense variants in nearby residues (C565R, C565Y, F572L, F572V, D573Y) have been reported in the Human Gene Mutation Database in association with SLC26A4-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, the V570I variant is a strong candidate for a pathogenic variant.
Counsyl RCV000673671 SCV000798899 uncertain significance Pendred syndrome 2018-03-30 no assertion criteria provided clinical testing

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