ClinVar Miner

Submissions for variant NM_000441.2(SLC26A4):c.845G>A (p.Cys282Tyr) (rs111033454)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Hearing Loss Variant Curation Expert Panel RCV001171537 SCV001334322 likely pathogenic Pendred syndrome 2020-02-19 reviewed by expert panel curation The p.Cys282Tyr variant in SLC26A4 is present in 0.0053% of European (non-Finnish) chromosomes by gnomAD v2.1.1, which is a low enough frequency to apply PM2 based on the thresholds defined by the ClinGen Hearing Loss expert Panel for autosomal recessive hearing loss (PM2). The REVEL computational prediction analysis tool produced a score of 0.719, which is above the threshold necessary to apply PP3. This variant has been detected in 3 probands with hearing loss. For all of the patients, a pathogenic or suspected-pathogenic variant was observed in trans (PM3_Strong, PMID:26969326, Partners LMM unpublished data SCV000060163.6, EGL Genetic Diagnostics unpublished data SCV000343642.4). At least one proband with this variant displayed features of sensorineural hearing loss and enlarged vestibular aqueduct, a phenotype specific for Pendred syndrome (PP4, PMID:26969326). Functional studies including fluorescence assays have demonstrated that this variant impacts protein function (PS3_Supporting; PMID:26752218). In summary, this variant meets criteria to be classified as likely pathogenic for autosomal recessive Pendred syndrome based on the ACMG/AMP criteria applied as specified by the Hearing Loss Expert Panel (PM3_Strong, PM2, PP3, PP4, PS3_Supporting).
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000036508 SCV000060163 likely pathogenic Rare genetic deafness 2015-06-19 criteria provided, single submitter clinical testing The p.Cys282Tyr variant in SLC26A4 has been identified by our laboratory in 2 in dividuals with hearing loss, one of whom also had EVA and carried a second, path ogenic SLC26A4 variant. This variant has also been identified in 2/66676 Europea n chromosomes by the Exome Aggregation Consortium (http://exac.broadinstitute.or g; dbSNP rs111033454). Although this variant has been seen in the general popula tion, its frequency is low enough to be consistent with a recessive carrier freq uency. Computational prediction tools and conservation analysis suggest that thi s variant may impact the protein, though this information is not predictive enou gh to determine pathogenicity. In summary, due to its identification in combinat ion with a reported pathogenic variant in an individual with hearing loss and EV A, the p.Cys282Tyr variant is likely pathogenic; however, additional studies are required to fully establish its clinical significance.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000396295 SCV000343642 uncertain significance not provided 2016-08-30 criteria provided, single submitter clinical testing

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