ClinVar Miner

Submissions for variant NM_000441.2(SLC26A4):c.200C>G (p.Thr67Ser) (rs111033240)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Hearing Loss Variant Curation Expert Panel RCV000671610 SCV001438403 likely benign Pendred syndrome 2020-09-22 reviewed by expert panel curation The c.200C>G (p.Thr67Ser) variant in SLC26A4 was present in 0.011% (2/18,394) of East Asian alleles in gnomAD v2. Although this frequency is low enough to meet PM2_Supporting, the ClinGen Hearing Loss Expert Panel believes that the evidence that this variant is likely benign outweighs the low allele frequency in population databases. This variant has been observed in cis with p.Leu236Val, which the Hearing Loss Expert Panel has classified as likely pathogenic, in at least 6 probands (BP2; PMID: 30113565, 30268946, Laboratory for Molecular Medicine internal data, ClinVar SCV000060121.6). It has been identified in at least 3 other probands with hearing loss with another pathogenic variant in SLC26A4 or in the homozygous state and segregated with disease in 1 additional family member (PMID: 18250610, 26969326, 22796198). Two probands with this variant displayed both sensorineural hearing loss and EVA, features highly specific for SLC26A4. Conservation analyses suggest that this variant may not impact the protein (BP4). Due to the possibility that the p.Thr67Ser and p.Leu236Val variants constitute a haplotype and the latter variant is driving pathogenicity, PM3, PP1, and PP4 were not applied. In summary, the p.Thr67Ser variant in SLC26A4 variant meets criteria to be considered likely benign. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: BP2, BP4.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000036466 SCV000060121 likely benign not specified 2015-11-08 criteria provided, single submitter clinical testing The p.Thr67Ser variant was found in cis with the p.Leu236Val variant, which was found in compound heterozygosity (with p.Thr99fs) in an Asian individual with h earing loss and bilateral temporal bone abnormalities and then segregated across five meioses to a distant relative where it was found in homozygosity in two si blings with congenital hearing loss and a paternal family history of hearing los s. Both variants are extremely rare (ExAC: p.Thr67Ser 1/11578 Latino and p.Leu2 36Val 4/11578 Latino ). This variant has been classified as likely benign given that it occurs at a poorly conserved residue with several mammals having a serin e at this position.
GeneDx RCV000036466 SCV000521212 likely benign not specified 2017-01-10 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Counsyl RCV000671610 SCV000796598 uncertain significance Pendred syndrome 2017-12-28 criteria provided, single submitter clinical testing
Invitae RCV001071424 SCV001236729 pathogenic not provided 2020-09-23 criteria provided, single submitter clinical testing This sequence change replaces threonine with serine at codon 67 of the SLC26A4 protein (p.Thr67Ser). The threonine residue is weakly conserved and there is a small physicochemical difference between threonine and serine. This variant is present in population databases (rs111033240, ExAC 0.009%). This variant has been observed in several individuals and families affected with Pendred syndrome (PMID: 18250610, 26969326, 22796198). 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: 43531). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: Tolerated; PolyPhen-2: Benign; Align-GVGD: Class C0. The serine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. For these reasons, this variant has been classified as Pathogenic.

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