Submissions for variant NM_000441.2(SLC26A4):c.1694G>A (p.Cys565Tyr)

gnomAD frequency: 0.00001  dbSNP: rs111033257

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Hearing Loss Variant Curation Expert Panel	RCV000666339	SCV004041585	likely pathogenic	Pendred syndrome	2023-07-19	reviewed by expert panel	curation	The c.1694G>A variant in SLC26A4 is a missense variant predicted to cause substitution of cysteine by tyrosine at amino acid 565 (p.Cys565Tyr). The highest population minor allele frequency in gnomAD v2.1.1 is 0.006% (1/15418) in European (non-Finnish) population, which is lower than the ClinGen Hearing Loss VCEP threshold less than or equal to 0.00007 (0.007%) for PM2_Supporting, meeting this criterion (PM2_Supporting). Radio isotope assays in Xenopus oocytes and HEK293T cell lines demonstrated that cells transfected with mutant SLC26A4 show a statistically significant decreased efflux of iodide compared to wildtype pendrin indicating that this variant impacts protein function (PS3_Supporting; PMID: 19204907, 31599023). This variant has been detected in at least 4 individuals with Pendred syndrome or nonsyndromic hearing loss with enlarged vestibular aqueduct (total of 3.5 PM3 points, PM3_Strong). One individual with Pendred syndrome was compound heterozygous with a pathogenic variant p.Q514R (ClinVar ID 43511, PMID: 19204907, 15689455). The second individual was a Pendred syndrome patient compound heterozygous with a pathogenic variant p.L236P (ClinVar ID 4817, PMID: 9618166). The third individual had nonsyndromic hearing loss with enlarged vestibular aqueduct which is highly specific for Pendred syndrome and was compound heterozygous with pathogenic p.H723R (ClinVar ID 4825, PMID: 14508505, PP4). The fourth individual had sensorineural hearing loss and enlarged vestibular aqueduct and was assumed compound heterozygous with pathogenic c.1342-2_1343dupAGTC (p.Leu450Glyfs*19) but phase unknown (Internal data from LMM). In summary, this variant has been classified as likely pathogenic for AR Pendred syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PM2_Supporting, PS3_Supporting, PM3_Strong, PP4. (VCEP specifications version 2; 07.19.2023).
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000036454	SCV000060109	likely pathogenic	Rare genetic deafness	2012-04-30	criteria provided, single submitter	clinical testing	The Cys565Tyr variant (SLC26A4) has been reported in one individual with Pendred syndrome and one individual with nonsyndromic hearing loss with enlarged vestib ular aqueducts (EVA), both of whom carried a second SLC26A4 variant, and was abs ent in 192 control chromosomes (Van Hauwe 1998, Tsukamoto 2003). In addition, th is variant has been identified in one individual with SNHL and EVA by our labora tory, who also carried a second pathogenic SLC26A4 variant. Studies have shown t hat the Cys565Tyr variant does not appear to impact certain protein functions (C hoi 2009, Ishihara 2010). However, these in vitro assays may not accurately repr esent biological function or fully assess all functions of the protein. In summa ry, this variant is likely to be pathogenic, though additional studies are requi red to fully establish the pathogenicity of this variant.
Counsyl	RCV000666339	SCV000790614	likely pathogenic	Pendred syndrome	2017-03-30	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001781350	SCV002023539	likely pathogenic	not provided	2020-10-11	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001781350	SCV002279665	pathogenic	not provided	2024-01-29	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 565 of the SLC26A4 protein (p.Cys565Tyr). This variant is present in population databases (rs111033257, gnomAD 0.007%). This missense change has been observed in individual(s) with clinical features of SLC26A4-related conditions (PMID: 9618166, 14508505, 19204907, 26346818). 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: 43519). 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 are conflicting or provide insufficient evidence to determine the effect of this variant on SLC26A4 function (PMID: 19204907, 20826203, 28341401, 33801843). This variant disrupts the p.Cys565 amino acid residue in SLC26A4. Other variant(s) that disrupt this residue have been observed in individuals with SLC26A4-related conditions (PMID: 16570074), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV001004646	SCV004201859	pathogenic	Autosomal recessive nonsyndromic hearing loss 4	2024-02-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000666339	SCV005062115	likely pathogenic	Pendred syndrome	2024-03-05	criteria provided, single submitter	clinical testing	Variant summary: SLC26A4 c.1694G>A (p.Cys565Tyr) results in a non-conservative amino acid change located in the STAS domain (IPR002645) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250542 control chromosomes (gnomAD). c.1694G>A has been reported in the literature in individuals affected with Pendred Syndrome or non-syndromic hearing loss with enlarged vestibular aqueduct who were compound heterozygous with pathogenic/likely pathogenic variants (van Hauwe_1998, Tsukamoto_2003, Choi_2009). These data indicate that the variant is likely to be associated with disease. Publications report experimental evidence evaluating an impact on protein function, finding that the variant results in a significant reduction in transport activity (Choi_2009, Wasana_2020). The following publications have been ascertained in the context of this evaluation (PMID: 9618166, 14508505, 19204907, 31599023). ClinVar contains an entry for this variant (Variation ID: 43519). A ClinGen expert panel has classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center	RCV001004646	SCV000994900	affects	Autosomal recessive nonsyndromic hearing loss 4	2019-08-20	no assertion criteria provided	literature only	in vitro experiment
Natera, Inc.	RCV000666339	SCV002080006	likely pathogenic	Pendred syndrome	2020-08-18	no assertion criteria provided	clinical testing