ClinVar Miner

Submissions for variant NM_000441.2(SLC26A4):c.1174A>T (p.Asn392Tyr) (rs201562855)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Division of Hearing and Balance Research,National Hospital Organization Tokyo Medical Center RCV000515717 SCV000611812 pathogenic Deafness, autosomal recessive 4, with enlarged vestibular aqueduct 2017-07-01 criteria provided, single submitter clinical testing
GeneDx RCV000657916 SCV000779683 pathogenic not provided 2018-05-10 criteria provided, single submitter clinical testing The N392Y missense variant has been previously reported in both the homozygous and compound heterozygous state in association with SLC26A4-related disorders (Huang et al., 2011; Luo et al., 2017; Reyes et al., 2009). Functional studies report that N392Y resulted in the change of intracellular localization of the protein and the loss of anion transporter activity (Ishihara et al., 2010). The variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. In summary, we consider this to be a pathogenic variant.
Invitae RCV000657916 SCV001224335 pathogenic not provided 2020-08-21 criteria provided, single submitter clinical testing This sequence change replaces asparagine with tyrosine at codon 392 of the SLC26A4 protein (p.Asn392Tyr). The asparagine residue is highly conserved and there is a large physicochemical difference between asparagine and tyrosine. This variant is present in population databases (rs201562855, ExAC 0.01%). This variant has been observed in individual(s) with nonsyndromic hearing loss and enlargement of the vestibular aqueduct (PMID: 19786220, 21961810, 17718863). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 446453). This variant has been reported to affect SLC26A4 protein function (PMID: 20826203). For these reasons, this variant has been classified as Pathogenic.
Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery,Institute of Otolaryngology, Chinese PLA General Hospital RCV000515717 SCV000902368 likely pathogenic Deafness, autosomal recessive 4, with enlarged vestibular aqueduct 2019-02-26 no assertion criteria provided case-control
National Institute of Sensory Organs,National Hospital Organization Tokyo Medical Center RCV000515717 SCV000994882 affects Deafness, autosomal recessive 4, with enlarged vestibular aqueduct 2019-08-20 no assertion criteria provided clinical testing in vitro experiment

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