Submissions for variant NM_000441.2(SLC26A4):c.200C>G (p.Thr67Ser)

gnomAD frequency: 0.00002  dbSNP: rs111033240

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Hearing Loss Variant Curation Expert Panel	RCV000671610	SCV001438403	likely benign	Pendred syndrome	2020-09-22	reviewed by expert panel	curation	The c.200C>G (p.Thr67Ser) variant in SLC26A4 was present in 0.011% (2/18,394) of East Asian alleles in gnomAD v2. Although this frequency is low enough to meet PM2_Supporting, the ClinGen Hearing Loss Expert Panel believes that the evidence that this variant is likely benign outweighs the low allele frequency in population databases. This variant has been observed in cis with p.Leu236Val, which the Hearing Loss Expert Panel has classified as likely pathogenic, in at least 6 probands (BP2; PMID: 30113565, 30268946, Laboratory for Molecular Medicine internal data, ClinVar SCV000060121.6). It has been identified in at least 3 other probands with hearing loss with another pathogenic variant in SLC26A4 or in the homozygous state and segregated with disease in 1 additional family member (PMID: 18250610, 26969326, 22796198). Two probands with this variant displayed both sensorineural hearing loss and EVA, features highly specific for SLC26A4. Conservation analyses suggest that this variant may not impact the protein (BP4). Due to the possibility that the p.Thr67Ser and p.Leu236Val variants constitute a haplotype and the latter variant is driving pathogenicity, PM3, PP1, and PP4 were not applied. In summary, the p.Thr67Ser variant in SLC26A4 variant meets criteria to be considered likely benign. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: BP2, BP4.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000036466	SCV000060121	likely benign	not specified	2015-11-08	criteria provided, single submitter	clinical testing	The p.Thr67Ser variant was found in cis with the p.Leu236Val variant, which was found in compound heterozygosity (with p.Thr99fs) in an Asian individual with h earing loss and bilateral temporal bone abnormalities and then segregated across five meioses to a distant relative where it was found in homozygosity in two si blings with congenital hearing loss and a paternal family history of hearing los s. Both variants are extremely rare (ExAC: p.Thr67Ser 1/11578 Latino and p.Leu2 36Val 4/11578 Latino ). This variant has been classified as likely benign given that it occurs at a poorly conserved residue with several mammals having a serin e at this position.
GeneDx	RCV001071424	SCV000521212	likely benign	not provided	2019-11-25	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 18250610, 24599119, 19040761, 19744334, 22796198, 17851929, 26969326, 30245029)
Counsyl	RCV000671610	SCV000796598	uncertain significance	Pendred syndrome	2017-12-28	criteria provided, single submitter	clinical testing
Invitae	RCV001071424	SCV001236729	pathogenic	not provided	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with serine, which is neutral and polar, at codon 67 of the SLC26A4 protein (p.Thr67Ser). This variant is present in population databases (rs111033240, gnomAD 0.01%). This missense change has been observed in individual(s) with Pendred syndrome (PMID: 18250610, 22796198, 26969326). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 43531). 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 not expected to disrupt SLC26A4 protein function with a negative predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital	RCV000036466	SCV001984738	likely benign	not specified	2020-11-03	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003964849	SCV004783813	likely benign	SLC26A4-related condition	2021-04-16	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).