Submissions for variant NM_000441.2(SLC26A4):c.317C>T (p.Ala106Val)

gnomAD frequency: 0.00001  dbSNP: rs1562822565

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002532186	SCV003473149	likely pathogenic	not provided	2022-06-01	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 106 of the SLC26A4 protein (p.Ala106Val). This missense change has been observed in individual(s) with deafness (PMID: 30303587). 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. This variant disrupts the p.Ala106 amino acid residue in SLC26A4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11317356, 29372807, 34170635). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 560910).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005240455	SCV005887918	likely pathogenic	Pendred syndrome	2025-01-08	criteria provided, single submitter	clinical testing	Variant summary: SLC26A4 c.317C>T (p.Ala106Val) results in a non-conservative amino acid change located in the Sulfate permease family domain (IPR011547) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251406 control chromosomes. c.317C>T has been reported in the literature in at least one homozygous individual from a family affected with nonsyndromic autosomal recessive hearing loss (e.g. Richard_2019). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A different variant located at the same codon (c.317C>A, p.Ala106Asp) has been classified as pathogenic, supporting a critical relevance of this residue to SLC26A4 protein function. The following publication has been ascertained in the context of this evaluation (PMID: 30303587). ClinVar contains an entry for this variant (Variation ID: 560910). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Center for Statistical Genetics, Columbia University	RCV000679838	SCV000804829	pathogenic	Deafness	2018-09-10	no assertion criteria provided	research
University of Washington Center for Mendelian Genomics, University of Washington	RCV001291243	SCV001479668	likely pathogenic	Hearing loss, autosomal recessive		no assertion criteria provided	research