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

gnomAD frequency: 0.00009  dbSNP: rs111033309

Total submissions: 16

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individuals were either homozygous for this variant or carried a second SLC26A4 variant (Coyle 1998, Campbell 2001, LMM unpublished data).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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000801210	SCV000940976	pathogenic	not provided	2025-01-25	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). Invitae Evidence 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 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).
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	2024-03-28	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV001824586	SCV005673654	pathogenic	Autosomal recessive nonsyndromic hearing loss 4; Pendred syndrome	2024-04-04	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.
PreventionGenetics, part of Exact Sciences	RCV002291269	SCV005350249	pathogenic	SLC26A4-related disorder	2024-03-28	no assertion criteria provided	clinical testing	The SLC26A4 c.2015G>A variant is predicted to result in the amino acid substitution p.Gly672Glu. This variant has been reported to be causative for Pendred syndrome (Coyle et al. 1998. PubMed ID: 9618167; Campbell et al. 2001. PubMed ID: 11317356). Functional studies showed that this variant had reduced localization to the cell surface and abolished iodide efflux in an in vitro assay (Taylor et al. 2002. PubMed ID: 11932316). This variant is reported in 0.012% of alleles in individuals of African descent in gnomAD. This variant is interpreted as pathogenic.