ClinVar Miner

Submissions for variant NM_000441.2(SLC26A4):c.1234G>A (p.Val412Ile)

gnomAD frequency: 0.00012  dbSNP: rs111033527
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000036431 SCV000060086 uncertain significance not specified 2010-02-03 criteria provided, single submitter clinical testing
Counsyl RCV000670464 SCV000795318 uncertain significance Pendred syndrome 2017-11-14 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV001785457 SCV002027008 uncertain significance Autosomal recessive nonsyndromic hearing loss 4 2021-09-05 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV000670464 SCV002027009 uncertain significance Pendred syndrome 2021-09-05 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV002490496 SCV002804072 uncertain significance Autosomal recessive nonsyndromic hearing loss 4; Pendred syndrome 2022-01-04 criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV003137559 SCV003825644 uncertain significance not provided 2022-05-30 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000036431 SCV005381318 uncertain significance not specified 2024-08-06 criteria provided, single submitter clinical testing Variant summary: SLC26A4 c.1234G>A (p.Val412Ile) results in a conservative amino acid change located in the SLC26A/SulP transporter domain (IPR011547) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.2e-05 in 250822 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in SLC26A4 causing Pendred Syndrome (5.2e-05 vs 0.0035), allowing no conclusion about variant significance. c.1234G>A has been reported in the literature in the heterozygous state, with no second variant identified, in individuals affected with Pendred Syndrome/Enlarged Vestibular Aqueduct (e.g. Landa_2013, Pang_2015, May_2019). These reports do not provide unequivocal conclusions about association of the variant with Pendred Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function and found the variant has approximately 60% HCO3-/Cl- antiporter activity compared to the WT protein and was considered WT-like (Takahashi_2024). The following publications have been ascertained in the context of this evaluation (PMID: 23965030, 31633822, 26549381, 38474007). ClinVar contains an entry for this variant (Variation ID: 43499). Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx RCV003137559 SCV005626492 uncertain significance not provided 2024-07-12 criteria provided, single submitter clinical testing In silico analysis indicates that this missense variant does not alter protein structure/function; Identified as a single heterozygous variant in a patient belonging to a cohort with hearing impairment and either goitre or EVA in published literature (PMID: 23965030); This variant is associated with the following publications: (PMID: 38474007, 27884173, 26549381, 30245029, 23965030)
Natera, Inc. RCV000670464 SCV001459868 uncertain significance Pendred syndrome 2020-01-08 no assertion criteria provided clinical testing

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