ClinVar Miner

Submissions for variant NM_000441.2(SLC26A4):c.1265T>C (p.Val422Ala) (rs1057520369)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000417941 SCV000514665 likely pathogenic not provided 2018-09-17 criteria provided, single submitter clinical testing The V422A variant in the SLC26A4 gene has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. However, missense variants at this same codon (V422D and V422I) have been reported in the heterozygous state with a second pathogenic variant in individuals with SLC26A4-related disorders (Banghova et al., 2008; Zhao et al., 2014). Furthermore, missense variants in nearby residues (T420I, Q421K, Q421P, Q421R, Q421L, G424D, I426N) 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. The V422A 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 V422A 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 where amino acids with similar properties to Valine are tolerated across species. However, in silico analysis predicts this variant is probably damaging to the protein structure/function. The V422A variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded.
Illumina Clinical Services Laboratory,Illumina RCV001162714 SCV001324676 uncertain significance Pendred syndrome 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Clinical Services Laboratory,Illumina RCV001162715 SCV001324677 uncertain significance Deafness, autosomal recessive 4, with enlarged vestibular aqueduct 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

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