Submissions for variant NM_000441.2(SLC26A4):c.397T>A (p.Ser133Thr)

dbSNP: rs121908365

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000005105	SCV000791203	likely pathogenic	Pendred syndrome	2017-05-03	criteria provided, single submitter	clinical testing
King Laboratory, University of Washington	RCV001004622	SCV002059882	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 4	2020-08-01	criteria provided, single submitter	research	Analysis of patient-derived RNA indicates that SLC26A4 c.397T>A leads to skipping of exon 4 (111bp) in message, with loss of aa 102-138 of TM1 and TM2 (Abu Rayyan 2020). The variant is homozygous in a Palestinian child with severe to profound pre-lingual hearing loss (Abu Rayyan 2020). It is absent from 1300 Palestinian controls and from gnomAD v2.1.1.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001851661	SCV002227962	pathogenic	not provided	2022-02-18	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Pendred syndrome (PMID: 11919333, 12788906). 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: 4834). 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. Studies have shown that this missense change results in skipping of exon 4, but is expected to preserve the integrity of the reading-frame (PMID: 32747562). For these reasons, this variant has been classified as Pathogenic. This sequence change replaces serine, which is neutral and polar, with threonine, which is neutral and polar, at codon 133 of the SLC26A4 protein (p.Ser133Thr). RNA analysis indicates that this missense change induces altered splicing and likely results in a shortened protein product.
OMIM	RCV000005105	SCV000025281	pathogenic	Pendred syndrome	2003-06-01	no assertion criteria provided	literature only
National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center	RCV001004622	SCV000994866	affects	Autosomal recessive nonsyndromic hearing loss 4	2019-08-20	no assertion criteria provided	literature only	in vitro experiment