Submissions for variant NM_001126108.2(SLC12A3):c.1963C>T (p.Arg655Cys)

gnomAD frequency: 0.00001  dbSNP: rs747249619

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001042994	SCV001206704	pathogenic	not provided	2023-12-20	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 655 of the SLC12A3 protein (p.Arg655Cys). This variant is present in population databases (rs747249619, gnomAD 0.004%). This missense change has been observed in individuals with Gitelman syndrome (PMID: 9734597, 22214629, 23328711, 25422309). ClinVar contains an entry for this variant (Variation ID: 840885). 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%. This variant disrupts the p.Arg655 amino acid residue in SLC12A3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11168953, 22009145, 22934535, 24776766). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Molecular Biology Laboratory, Fundació Puigvert	RCV001281278	SCV001425256	likely pathogenic	Familial hypokalemia-hypomagnesemia	2020-02-01	criteria provided, single submitter	research
Genome-Nilou Lab	RCV001281278	SCV002055343	likely pathogenic	Familial hypokalemia-hypomagnesemia	2021-07-15	criteria provided, single submitter	clinical testing
GeneDx	RCV001042994	SCV002575220	likely pathogenic	not provided	2022-03-23	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 12686679, 22934535, 11168953, 22214629, 9734597, 30596175, 24776766, 31398183, 25422309, 23328711, 22009145, 31672324, 33532864)
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV001281278	SCV004046306	pathogenic	Familial hypokalemia-hypomagnesemia		criteria provided, single submitter	clinical testing	This variant has been previously reported as a compound heterozygous and homozygous change in patients with Gitelman syndrome (PMID: 31398183, 9734597, 22214629, 25422309, 23328711, 30596175). Different amino acid changes at the same residue (p.Arg655His, p.Arg655Leu) have been previously reported in individuals with Gitelman syndrome (PMID:22934535, 22009145, 11168953, 24776766, 31398183). The c.1963C>T (p.Arg655Cys) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.002789% (7/250982) and is absent in the homozygous state, thus it is presumed to be rare. The c.1963C>T (p.Arg655Cys) variant affects a moderately conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.1963C>T (p.Arg655Cys) variant is classified as Pathogenic.
Natera, Inc.	RCV001281278	SCV002089362	pathogenic	Familial hypokalemia-hypomagnesemia	2020-10-05	no assertion criteria provided	clinical testing