Submissions for variant NM_000111.3(SLC26A3):c.1181G>T (p.Ser394Ile)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003479789	SCV004223563	uncertain significance	not specified	2023-11-09	criteria provided, single submitter	clinical testing	Variant summary: SLC26A3 c.1181G>T (p.Ser394Ile) 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 251066 control chromosomes. c.1181G>T has been reported in the literature in multiple compound heterozygous individuals affected with Congenital secretory diarrhea (e.g. Amato_2017, Esposito_2021). 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. The following publications have been ascertained in the context of this evaluation (PMID: 28644346, 33567694). No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003553993	SCV004295512	pathogenic	not provided	2023-04-06	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. 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 SLC26A3 protein function. This missense change has been observed in individual(s) with congenital chloride diarrhea (PMID: 28644346, 33567694). 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. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 394 of the SLC26A3 protein (p.Ser394Ile).