Total submissions: 8
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
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, |
RCV000036508 | SCV000060163 | likely pathogenic | Rare genetic deafness | 2015-06-19 | criteria provided, single submitter | clinical testing | The p.Cys282Tyr variant in SLC26A4 has been identified by our laboratory in 2 in dividuals with hearing loss, one of whom also had EVA and carried a second, path ogenic SLC26A4 variant. This variant has also been identified in 2/66676 Europea n chromosomes by the Exome Aggregation Consortium (http://exac.broadinstitute.or g; dbSNP rs111033454). Although this variant has been seen in the general popula tion, its frequency is low enough to be consistent with a recessive carrier freq uency. Computational prediction tools and conservation analysis suggest that thi s variant may impact the protein, though this information is not predictive enou gh to determine pathogenicity. In summary, due to its identification in combinat ion with a reported pathogenic variant in an individual with hearing loss and EV A, the p.Cys282Tyr variant is likely pathogenic; however, additional studies are required to fully establish its clinical significance. |
Eurofins Ntd Llc |
RCV000396295 | SCV000343642 | uncertain significance | not provided | 2016-08-30 | criteria provided, single submitter | clinical testing | |
Fulgent Genetics, |
RCV002477085 | SCV002798972 | likely pathogenic | Autosomal recessive nonsyndromic hearing loss 4; Pendred syndrome | 2021-10-08 | criteria provided, single submitter | clinical testing | |
Gene |
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 | 2023-08-07 | criteria provided, single submitter | clinical testing | |
Invitae | 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, |
RCV001171537 | SCV002079978 | likely pathogenic | Pendred syndrome | 2020-10-08 | no assertion criteria provided | clinical testing |