Submissions for variant NM_000441.2(SLC26A4):c.397T>C (p.Ser133Pro)

gnomAD frequency: 0.00001  dbSNP: rs121908365

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002010951	SCV002289504	pathogenic	not provided	2023-08-04	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 133 of the SLC26A4 protein (p.Ser133Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Pendred syndrome (Invitae). ClinVar contains an entry for this variant (Variation ID: 1502303). 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. This variant disrupts the p.Ser133 amino acid residue in SLC26A4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11919333, 12788906). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003323972	SCV004028705	uncertain significance	not specified	2023-07-13	criteria provided, single submitter	clinical testing	Variant summary: SLC26A4 c.397T>C (p.Ser133Pro) results in a non-conservative amino acid change located in the SLC26A/SulP transporter 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 251354 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.397T>C in individuals affected with Pendred Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. However, a reputable clinical laboratory reported the variant in affected individual(s) in ClinVar. In addition, other missense changes affecting the same amino acid (p.Ser133Thr/Leu) have been reported in multiple affected individuals (HGMD), suggesting that this residue may be critical for normal function of the protein. One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.