ClinVar Miner

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

gnomAD frequency: 0.00009  dbSNP: rs111033309
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Total submissions: 15
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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 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individuals were either homozygous for this variant or carried a second SLC26A4 variant (Coyle 1998, Campbell 2001, LMM unpublished data).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 Laboratory Services, 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 2024-01-01 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 672 of the SLC26A4 protein (p.Gly672Glu). This variant is present in population databases (rs111033309, gnomAD 0.01%). This missense change has been observed in individual(s) with SLC26A4-related conditions (PMID: 9618167, 11317356, 21366435). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 43532). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SLC26A4 protein function. Experimental studies have shown that this missense change affects SLC26A4 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 Laboratory Services, Illumina RCV001161291 SCV001323153 uncertain significance Autosomal recessive nonsyndromic hearing loss 4 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.
GeneDx RCV000801210 SCV001820379 pathogenic not provided 2022-12-28 criteria provided, single submitter clinical testing Published functional studies demonstrate that the p.(G672E) variant abolishes normal protein function (Taylor et al., 2002); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 9618167, 11317356, 33199029, 21366435, 32165640, 11932316)
Genome-Nilou Lab RCV001161291 SCV002027395 likely pathogenic Autosomal recessive nonsyndromic hearing loss 4 2021-09-05 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV000778812 SCV002027406 likely pathogenic Pendred syndrome 2021-09-05 criteria provided, single submitter clinical testing
Genetics and Molecular Pathology, SA Pathology RCV000778812 SCV002556413 pathogenic Pendred syndrome 2022-02-21 criteria provided, single submitter clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center RCV002291269 SCV002583766 pathogenic SLC26A4-related disorder 2022-07-25 criteria provided, single submitter clinical testing PS3, PM2, PM3, PP1, PP3
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000778812 SCV002598622 pathogenic Pendred syndrome 2022-09-02 criteria provided, single submitter clinical testing Variant summary: SLC26A4 c.2015G>A (p.Gly672Glu) results in a non-conservative amino acid change located in the STAS 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 6.4e-05 in 251180 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in SLC26A4 causing Pendred Syndrome (6.4e-05 vs 0.0035), allowing no conclusion about variant significance. c.2015G>A has been reported in the literature in multiple individuals affected with Pendred Syndrome or hearing loss. These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and showed that G672E abolished normal protein function at the cell surface (Taylor_2002). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and all classified this variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Molecular Diagnostics Lab, Nemours Children's Health, Delaware RCV000778812 SCV003935254 likely pathogenic Pendred syndrome 2020-05-15 criteria provided, single submitter clinical testing
Baylor Genetics RCV001161291 SCV004201830 pathogenic Autosomal recessive nonsyndromic hearing loss 4 2023-10-22 criteria provided, single submitter clinical testing
Natera, Inc. RCV000778812 SCV001459936 pathogenic Pendred syndrome 2020-09-16 no assertion criteria provided clinical testing
GenomeConnect, ClinGen RCV001824586 SCV002075032 not provided Autosomal recessive nonsyndromic hearing loss 4; Pendred syndrome no assertion provided phenotyping only Variant interpreted as Pathogenic and reported on 07-17-2019 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

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