ClinVar Miner

Submissions for variant NM_000441.2(SLC26A4):c.589G>A (p.Gly197Arg) (rs111033380)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001056927 SCV001221394 pathogenic not provided 2019-12-15 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 197 of the SLC26A4 protein (p.Gly197Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs111033380, ExAC 0.01%). This variant has been observed in individual(s) with SLC26A4-related conditions (PMID: 21961810, 23385134, 28576516, 17718863). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 43562). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C1). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001553550 SCV001774439 pathogenic Pendred syndrome 2021-08-02 criteria provided, single submitter clinical testing Variant summary: SLC26A4 c.589G>A (p.Gly197Arg) results in a non-conservative amino acid change located in the SLC26A/SulP transporter domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251396 control chromosomes. c.589G>A has been reported in the literature in multiple individuals affected with SLC26A4-related conditions (e.g. Chai_2013, Luo_2020). These data indicate that the variant is very likely to be associated with disease. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000036500 SCV000060155 likely pathogenic Rare genetic deafness 2008-01-02 no assertion criteria provided clinical testing
Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery,Institute of Otolaryngology, Chinese PLA General Hospital RCV000770858 SCV000902364 likely pathogenic Deafness, autosomal recessive 4, with enlarged vestibular aqueduct 2019-02-26 no assertion criteria provided case-control

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