Submissions for variant NM_001126108.2(SLC12A3):c.2515G>A (p.Asp839Asn)

gnomAD frequency: 0.00001  dbSNP: rs1298687889

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002010744	SCV002289830	pathogenic	not provided	2023-10-25	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 848 of the SLC12A3 protein (p.Asp848Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Gitelman syndrome (PMID: 16837915, 31183353, 33348466, 34657521). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as D839N. ClinVar contains an entry for this variant (Variation ID: 1499557). 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.
European Hospital Georges Pompidou Genetics Department, Assistance Publique - Hôpitaux de Paris AP-HP	RCV002243505	SCV002513818	likely pathogenic	Familial hypokalemia-hypomagnesemia	2022-04-27	criteria provided, single submitter	clinical testing	ACMG criteria used:PM1 PM2 PM3 PP3 PP5