ClinVar Miner

Submissions for variant NM_000441.2(SLC26A4):c.1281TGC[1] (p.Ala429del) (rs111033306)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000036434 SCV000060089 pathogenic Rare genetic deafness 2018-10-04 criteria provided, single submitter clinical testing The p.Ala429del variant in SLC26A4 has been reported in at least 10 individuals with hearing loss, most of who were also reported to have temporal bone abnormal ities and/or Pendred syndrome (Coyle 1998, Prasad 2004, Dahl 2013, Rendtorff 201 3, Sloan-Heggen 2016, LMM data). At least 6 of these individuals were compound h eterozygous for additional pathogenic variants in SLC26A4 (Dahl 2013, Rentorff 2 013, Sloan-Heggen 2016, LMM data). This variant has also been identified in 0.01 % (14/126202) of European chromosomes by gnomAD (http://gnomad.broadinstitute.or g); however, its frequency is low enough to be consistent with a recessive carri er frequency. This variant is a deletion of 1 amino acid at position 429 and is not predicted to alter the protein reading frame. In summary, this variant meets our criteria to be classified as pathogenic for hearing loss with EVA and/or Pe ndred syndrome in an autosomal recessive manner based on its occurrence with pat hogenic SLC26A4 variants in several compound heterozygous affected individuals. ACMG/AMP Criteria applied: PM3_Very Strong, PM2_Supporting, PM4_Supporting.
Counsyl RCV000169051 SCV000220211 likely pathogenic Pendred syndrome 2014-04-01 criteria provided, single submitter literature only
Baylor Genetics RCV000169051 SCV001163094 likely pathogenic Pendred syndrome criteria provided, single submitter clinical testing
Invitae RCV001209562 SCV001381002 likely pathogenic not provided 2020-10-14 criteria provided, single submitter clinical testing This variant, c.1284_1286del, results in the deletion of 1 amino acid(s) of the SLC26A4 protein (p.Ala429del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs775837019, ExAC 0.01%). This variant has been observed in individuals affected with Pendred syndrome (PMID: 26969326, 21366435, 25394566, 23336812). ClinVar contains an entry for this variant (Variation ID: 43501). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Natera, Inc. RCV000169051 SCV001459925 pathogenic Pendred syndrome 2020-09-16 no assertion criteria provided clinical testing

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