ClinVar Miner

Submissions for variant NM_000441.2(SLC26A4):c.1204G>A (p.Val402Met)

dbSNP: rs397516414
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Hearing Loss Variant Curation Expert Panel RCV001171536 SCV001334321 pathogenic Pendred syndrome 2020-02-19 reviewed by expert panel curation The p.Val402Met variant in SLC26A4 was absent from gnomAD v2.1.1 and v3 (PM2). This variant has been detected in 2 probands with hearing loss. For both patients, a pathogenic or suspected-pathogenic variant was observed in trans (PM3_Strong, PMID:19204907, Partners LMM unpublished data SCV000060082.6). The variant has been reported to segregate in one affected family member (PP1, PMID:19204907). At least one proband with this variant displayed features of sensorineural hearing loss and enlarged vestibular aqueduct, a phenotype specific for Pendred syndrome (PP4, LMM unpublished data SCV000060082.6). Functional studies including fluorescence assays have demonstrated that this variant impacts protein function (PS3_Supporting; PMID:19204907). The REVEL computational prediction analysis tool produced a score of 0.77, which is above the threshold necessary to apply PP3. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Pendred syndrome based on the ACMG/AMP criteria applied as specified by the Hearing Loss Expert Panel (PM3_Strong, PM2, PP1, PP3, PP4, PS3_Supporting).
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000036427 SCV000060082 likely pathogenic Rare genetic deafness 2016-11-17 criteria provided, single submitter clinical testing The p.Val402Met variant in SLC26A4 has been identified in the compound heterozyg ous state with another pathogenic variant in SLC26A4 in two siblings with enlarg ed vestibular aqueduct (Choi 2009) and in an individual with hearing loss tested by our laboratory. This variant has not been reported in large population studi es. A study has shown that the p.Val402Met variant may impact protein function ( Choi 2009). In summary, although additional studies are required to fully establ ish its clinical significance, this variant is likely pathogenic.
GeneDx RCV002272039 SCV002558571 pathogenic not provided 2022-01-26 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect due to loss of anion transporter activity of the variant protein (Choi BY et al., 2009); Reported as pathogenic by the ClinGen Hearing Loss Expert Panel but additional evidence is not available (ClinVar SCV001334321.1; Oza et al., 2018); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27771369, 20128824, 19204907, 30311386)
Baylor Genetics RCV003473262 SCV004204223 likely pathogenic Autosomal recessive nonsyndromic hearing loss 4 2023-01-23 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001171536 SCV005422309 likely pathogenic Pendred syndrome 2024-10-14 criteria provided, single submitter clinical testing Variant summary: SLC26A4 c.1204G>A (p.Val402Met) results in a conservative amino acid change located in the SLC26A/SulP transporter domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250984 control chromosomes. c.1204G>A has been reported in the literature in two compound heterozygous siblings affected with hearing loss and enlargement of the vestibular aqueduct (e.g., Choi_2009). These data indicate that the variant may be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function (e.g., Choi_2009, Takahashi_2024). The most pronounced variant effect results in <10% of normal anion transport function in a fluorometric antiport assay (e.g., Takahashi_2024). The following publications have been ascertained in the context of this evaluation (PMID: 19204907, 38474007). ClinVar contains an entry for this variant (Variation ID: 43495). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Natera, Inc. RCV001171536 SCV002079992 likely pathogenic Pendred syndrome 2021-07-26 no assertion criteria provided clinical testing

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