Submissions for variant NM_000441.2(SLC26A4):c.2153T>C (p.Phe718Ser)

gnomAD frequency: 0.00005  dbSNP: rs750834241

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000441837	SCV000521214	uncertain significance	not provided	2019-09-10	criteria provided, single submitter	clinical testing	Identified as heterozygous in individuals with hearing loss but without an identified second SLC26A4 variant (PMID: 21366435, 23965030); 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: 21366435, 23965030, 27068579)
Myriad Genetics, Inc.	RCV000984219	SCV002060351	uncertain significance	Pendred syndrome	2021-10-01	criteria provided, single submitter	clinical testing	NM_000441.1(SLC26A4):c.2153T>C(F718S) is a missense variant classified as a variant of uncertain significance in the context of Pendred syndrome. F718S has been observed in cases with relevant disease (PMID: 27068579, 23965030, 21366435). Functional assessments of this variant are not available in the literature. F718S has been observed in population frequency databases (gnomAD: NFE 0.01%). In summary, there is insufficient evidence to classify NM_000441.1(SLC26A4):c.2153T>C(F718S) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002282143	SCV002571862	uncertain significance	not specified	2022-08-08	criteria provided, single submitter	clinical testing	Variant summary: SLC26A4 c.2153T>C (p.Phe718Ser) results in a non-conservative amino acid change located in the STAS domain (IPR002645) 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 3.2e-05 in 251316 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2153T>C has been reported in the literature in one biallelic individual affected with Hearing Loss (Sommen_2016), and two monoallelic individuals with suspected Pendred Syndrome (Landa_2013, Mercer_2011). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters have assessed the variant since 2014: two classified the variant as of uncertain significance and one as likely pathogenic. Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000441837	SCV003294380	likely pathogenic	not provided	2024-05-06	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 718 of the SLC26A4 protein (p.Phe718Ser). This variant is present in population databases (rs750834241, gnomAD 0.006%). This missense change has been observed in individual(s) with autosomal recessive deafness (PMID: 21366435, 23965030, 27068579; Invitae). ClinVar contains an entry for this variant (Variation ID: 381687). 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. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.