ClinVar Miner

Submissions for variant NM_000441.2(SLC26A4):c.2015G>A (p.Gly672Glu) (rs111033309)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000036467 SCV000060122 pathogenic Rare genetic deafness 2015-02-19 criteria provided, single submitter clinical testing The p.Gly672Glu variant in SLC26A4 has been reported in 3 probands with the clin ical features of Pendred syndrome, and was identified by our laboratory in 1 ind ividual with hearing loss and EVA. The variant segregated with Pendred syndrome or hearing loss in 4 affected family members across 3 families, and all affected individuals were either homozygous for this variant or carried a second SLC26A4 variant (Coyle 1998, Campbell 2001, LMM unpublished data). In addition, functio nal analysis revealed that this variant causes the protein to be retained in the cytoplasm and abolishes its normal function at the cell surface (Taylor 2002). This variant was also identified in 5/66278 European chromosomes by the Exome Ag gregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs111033309); however, this frequency is low enough to be consistent with a recessive carrier frequency. In summary, the p.Gly672Glu variant meets our criteria to be classifi ed as pathogenic.
Illumina Clinical Services Laboratory,Illumina RCV000778812 SCV000915192 pathogenic Pendred syndrome 2019-01-10 criteria provided, single submitter clinical testing The SLC26A4 c.2015G>A (p.Gly672Glu) missense variant has been reported in two studies and is found in a total of seven probands from three families, including two in a homozygous state and five in a compound heterozygous state (Coyle et al. 1998; Campbell et al. 2011). All probands had clinical features of Pendred syndrome, including hearing loss and temporal bone abnormalities. The variant was absent from 150 control chromosomes and is reported at a frequency of 0.00035 in the European American population of the Exome Sequencing Project. Taylor et al. (2002) performed functional studies on the p.Gly672Glu variant and found that the localization of the variant protein to the membrane is partial, and the function of the protein that reached the cell surface was abolished. Based on the collective evidence, the p.Gly672Glu variant is classified as pathogenic for Pendred syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV000801210 SCV000940976 pathogenic not provided 2020-09-09 criteria provided, single submitter clinical testing This sequence change replaces glycine with glutamic acid at codon 672 of the SLC26A4 protein (p.Gly672Glu). The glycine residue is moderately conserved and there is a moderate physicochemical difference between glycine and glutamic acid. This variant is present in population databases (rs111033309, ExAC 0.02%). This variant has been observed to segregate with SLC26A4-related conditions in a family (PMID: 9618167), and has been observed in several other unrelated individuals with SLC26A4-related conditions (PMID: 11317356, 21366435). ClinVar contains an entry for this variant (Variation ID: 43532). Experimental studies have shown that this missense change has a deleterious effect on protein function (PMID: 11932316). For these reasons, this variant has been classified as Pathogenic.
UNC Molecular Genetics Laboratory,University of North Carolina at Chapel Hill RCV000778812 SCV001251491 likely pathogenic Pendred syndrome criteria provided, single submitter research The SLC26A4 c.2015G>A (p.G672E) variant has been observed in the homozygous or compound heterozygous state in 3 families with Pendred syndrome or a dilated vestibular aqueduct (PMID: 9618167;11317356).
Illumina Clinical Services Laboratory,Illumina RCV001161291 SCV001323153 uncertain significance Deafness, autosomal recessive 4, with enlarged vestibular aqueduct 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Natera, Inc. RCV000778812 SCV001459936 pathogenic Pendred syndrome 2020-09-16 no assertion criteria provided clinical testing

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