Submissions for variant NM_000441.2(SLC26A4):c.1541A>G (p.Gln514Arg)

gnomAD frequency: 0.00006  dbSNP: rs111033316

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000320959	SCV000329521	pathogenic	not provided	2024-10-07	criteria provided, single submitter	clinical testing	Published functional studies demonstrate mislocalization of the SLC26A4 protein, however the effect on ion transport was not assessed (PMID: 19204907); 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: 33199029, 23555729, 26969326, 25394566, 19318451, 15689455, 19204907, 34515852, 38426810)
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000507599	SCV000605151	pathogenic	not specified	2017-03-02	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000320959	SCV001225432	pathogenic	not provided	2024-08-23	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 514 of the SLC26A4 protein (p.Gln514Arg). This variant is present in population databases (rs111033316, gnomAD 0.01%). This missense change has been observed in individuals with Pendred syndrome (PMID: 15689455, 25394566, 26969326). ClinVar contains an entry for this variant (Variation ID: 43511). 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) indicates that this missense variant is expected to disrupt SLC26A4 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects SLC26A4 function (PMID: 19204907). This variant disrupts the p.Gln514 amino acid residue in SLC26A4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18285825, 19017801). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Genome-Nilou Lab	RCV000666548	SCV002026938	pathogenic	Pendred syndrome	2021-09-05	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003473266	SCV004201841	pathogenic	Autosomal recessive nonsyndromic hearing loss 4	2024-03-15	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005031472	SCV005673635	pathogenic	Autosomal recessive nonsyndromic hearing loss 4; Pendred syndrome	2024-01-11	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000036445	SCV000060100	likely pathogenic	Rare genetic deafness	2009-06-03	no assertion criteria provided	clinical testing
Counsyl	RCV000666548	SCV000790855	likely pathogenic	Pendred syndrome	2017-04-12	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004737174	SCV005361446	pathogenic	SLC26A4-related disorder	2024-05-01	no assertion criteria provided	clinical testing	The SLC26A4 c.1541A>G variant is predicted to result in the amino acid substitution p.Gln514Arg. This variant has been reported as causative for Pendred syndrome (Pryor et al 2005. PubMed ID: 15689455; Choi et al 2009. PubMed ID: 19204907; Table S3, Sloan-Heggen et al 2016. PubMed ID: 26969326; Soh et al 2014. PubMed ID: 25394566). This variant is reported in 0.012% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.