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	likely pathogenic	not provided	2016-08-18	criteria provided, single submitter	clinical testing	The F718S variant in the SLC26A4 gene has been reported previously in association with hearing loss, in an individual who was heterozygous for the F718S and another variant (Sommen et al., 2016), and in individuals with were heterozygous for the F718S variant and no second variant identified (Mercer et al., 2011; Landa et al., 2013). The F718S variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The F718S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position where amino acids with similar properties to Phenylalanine are tolerated across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in nearby residues (R714K, K715N, D716G, T721M, H723Y, H723D, H723R) have been reported in the Human Gene Mutation Database in association with hearing loss (Stenson et al., 2014), supporting the functional importance of this region of the protein. The F718S variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded.
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.
Invitae	RCV000441837	SCV003294380	uncertain significance	not provided	2021-08-13	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine with serine at codon 718 of the SLC26A4 protein (p.Phe718Ser). The phenylalanine residue is highly conserved and there is a large physicochemical difference between phenylalanine and serine. This variant is present in population databases (rs750834241, ExAC 0.005%). This missense change has been observed in individual(s) with deafness with enlarged vestibular aqueduct (PMID: 21366435, 27068579). ClinVar contains an entry for this variant (Variation ID: 381687). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.