Submissions for variant NM_001126108.2(SLC12A3):c.2800C>T (p.Arg934Trp)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002654662	SCV003521478	pathogenic	not provided	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 943 of the SLC12A3 protein (p.Arg943Trp). This variant is present in population databases (rs201721269, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of Gitelman syndrome (PMID: 21415153; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 2200213). 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 SLC12A3 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003988065	SCV004803683	likely pathogenic	Familial hypokalemia-hypomagnesemia	2024-01-03	criteria provided, single submitter	clinical testing	Variant summary: SLC12A3 c.2827C>T (p.Arg943Trp) results in a non-conservative amino acid change located in the SLC12A transporter, C-terminal domain (IPR018491) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.8e-05 in 251446 control chromosomes (gnomAD). c.2827C>T has been reported in the literature in compound heterozygous and homozygous individuals affected with Familial Hypokalemia-Hypomagnesemia (Nicolet-Barousse_2004, Vargas-Poussou_2011, Glaudemans_2011, Blanchard_2019, Shen_2021). These data indicate that the variant is likely to 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: 31285285, 22009145, 15824853, 33382082, 21415153). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.