Submissions for variant NM_000441.2(SLC26A4):c.845G>A (p.Cys282Tyr)

gnomAD frequency: 0.00001  dbSNP: rs111033454

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Hearing Loss Variant Curation Expert Panel	RCV001171537	SCV001334322	likely pathogenic	Pendred syndrome	2023-01-24	reviewed by expert panel	curation	The c.845G>A (NM_000441.2) variant in SLC26A4 is a missense variant predicted to cause substitution of cysteine by tyrosine at amino acid 282 (p.Cys282Tyr). The highest population minor allele frequency in gnomAD v.2.1.1 is 0.000053 (6/113490 alleles) in the European non-Finnish population, which is lower than the ClinGen Hearing Loss threshold (<0.0007) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.719 which is above the threshold of 0.7, evidence that correlates with impact to SLC26A4 function (PP3). This variant has been detected in at least 4 individuals with hearing loss. Of those individuals, three were compound heterozygous for the variant and a pathogenic variant observed in trans and one had a rare VUS variant on other allele (c.1001+1G>A, c.233A > G, 3.25 PM3 points, PMID:26969326,33152970, SCV000060163.6, SCV000343642.4) (PM3_Strong). At least one proband with this variant displayed features of sensorineural hearing loss and enlarged vestibular aqueduct, a phenotype highly specific for Pendred syndrome (PP4, PMID:26969326,33152970, SCV000060163.6). Functional studies including fluorescence assays have demonstrated that this variant impacts protein function (PS3_Supporting; PMID:26752218). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive Pendred syndrome based on the ACMG/AMP criteria applied as specified by the Hearing Loss VCEP: PM2_Supporting, PP3, PM3_Strong, PP4, PS3_Supporting. (ClinGen Hearing Loss VCEP specifications version 2; 1/18/2023).
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000036508	SCV000060163	likely pathogenic	Rare genetic deafness	2022-06-30	criteria provided, single submitter	clinical testing	The p.Cys282Tyr variant in SLC26A4 has been identified in 5 individuals with hearing loss, two of which had EVA and carried a second, pathogenic SLC26A4 variant (Sloan-Heggen 2016 PMID: 26969326, De Moraes 2016 PMID: 26752218, Kinoglu 2020 PMID: 33152970, LMM data). It has also been identified in 0.004% (3/68020) of European chromosomes by gnomAD, v. 3 (http://gnomad.broadinstitute.org). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant was classified as Likely Pathogenic on Feb 19, 2020 by the ClinGen-approved Hearing Loss Variant Curation expert panel (Variation ID 43568). Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In vitro functional studies provide some evidence that this variant reduces function of the pendrin protein, however retains transport activity (de Moraes 2016 PMID: 26752218); however, these types of assays may not accurately represent biological function. In summary, due to its identification in combination with a reported pathogenic variant in an individual with hearing loss and EVA, the p.Cys282Tyr variant is likely pathogenic; however, additional studies are required to fully establish its clinical significance. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive Pendred syndrome. ACMG/AMP Criteria applied: PM3_Strong, PP3, PM2_P, PS3_Supporting.
Eurofins Ntd Llc (ga)	RCV000396295	SCV000343642	uncertain significance	not provided	2016-08-30	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002477085	SCV002798972	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 4; Pendred syndrome	2021-10-08	criteria provided, single submitter	clinical testing
GeneDx	RCV000396295	SCV004036263	likely pathogenic	not provided	2023-03-21	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a reduction in activity in transfected cells compared to wild type (De Moraes et al., 2016).; Reported in individuals with hearing loss who also harbored additional hearing loss associated variants (Sloan-Heggen et al., 2016; De Moraes et al., 2016; Kinglu et al., 2020; Baldyga et al., 2023); Not observed at significant frequency in large population cohorts (gnomAD); 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: 26752218, 36833263, 22995429, 26969326, 33152970)
Baylor Genetics	RCV003473272	SCV004201897	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 4	2024-03-25	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000396295	SCV004295487	pathogenic	not provided	2023-12-11	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 282 of the SLC26A4 protein (p.Cys282Tyr). This variant is present in population databases (rs111033454, gnomAD 0.004%). This missense change has been observed in individual(s) with clinical features of SLC26A4-related conditions (PMID: 26969326, 33152970; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 43568). 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) performed at Invitae indicates that this missense variant is expected to disrupt SLC26A4 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects SLC26A4 function (PMID: 26752218). For these reasons, this variant has been classified as Pathogenic.
Natera, Inc.	RCV001171537	SCV002079978	likely pathogenic	Pendred syndrome	2020-10-08	no assertion criteria provided	clinical testing