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	2024-03-20	reviewed by expert panel	curation	The c.200C>G (p.Thr67Ser) variant in SLC26A4 is a missense variant predicted to cause substitution of threonine by serine at amino acid 67. The highest population minor allele frequency in gnomAD v4.0.0 is 4/39700 alleles (0.0001008 or 0.01 %) in the East Asian population (PM2_supporting, BS1, and BA1 not met). The results from two predictors/lines of evidence, MaxEntScan and conservation analysis, with serine present at this residue in ten vertebrates, suggest that the variant does not impact SLC26A4 function (BP4). This variant has been observed in cis with the variant p.Leu236Val (c.706C>G) [PMIDs: 30113565, 30268946, Laboratory for Molecular Medicine internal data, ClinVar SCV000060121.6], which is classified as likely pathogenic by the ClinGen Hearing Loss VCEP, in at least six affected individuals (BP2). The variant has been seen in the homozygous and compound heterozygous (in trans, phase confirmed) state in at least three other individuals affected with hearing loss (PMIDs: 18250610, 22796198, 26969326). However, PM3 was not applied due to the fact that these individuals may also have carried the p.Leu236Val variant that was causative of the disorder. In summary, this variant meets the criteria to be classified as likely benign for autosomal recessive Pendred Syndrome, based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP (BP4, BP2; Version 2; 3/20/24).
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
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
Labcorp Genetics (formerly Invitae), Labcorp	RCV001071424	SCV001236729	pathogenic	not provided	2024-01-29	flagged submission	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.
PreventionGenetics, part of Exact Sciences	RCV004541096	SCV004783813	likely benign	SLC26A4-related disorder	2021-04-16	no assertion criteria provided	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).