Submissions for variant NM_001126108.2(SLC12A3):c.947G>C (p.Gly316Ala)

dbSNP: rs748920885

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001941712	SCV002234249	pathogenic	not provided	2024-11-25	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 316 of the SLC12A3 protein (p.Gly316Ala). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Gitelman syndrome (PMID: 17699451, 30138938). 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: 1454113). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt SLC12A3 protein function with a positive predictive value of 95%. This variant disrupts the p.Gly316 amino acid residue in SLC12A3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12112667, 17329572, 21415153). 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.
Fulgent Genetics, Fulgent Genetics	RCV002497870	SCV002776584	likely pathogenic	Familial hypokalemia-hypomagnesemia	2024-05-17	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV002497870	SCV003816341	likely pathogenic	Familial hypokalemia-hypomagnesemia	2022-12-07	criteria provided, single submitter	clinical testing
GeneDx	RCV001941712	SCV003921509	likely pathogenic	not provided	2022-10-31	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); 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: 30138938, 17699451, 17329572, 12112667, 26921350)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002497870	SCV004028612	pathogenic	Familial hypokalemia-hypomagnesemia	2023-07-11	criteria provided, single submitter	clinical testing	Variant summary: SLC12A3 c.947G>C (p.Gly316Ala) results in a non-conservative amino acid change located in the amino acid permease/SLC12A domain (IPR004841) 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 251290 control chromosomes (gnomAD v2.1, Exomes dataset). c.947G>C has been reported in the literature in both compound heterozygous and homozygous individuals affected with Familial Hypokalemia-Hypomagnesemia/Gitelman Syndrome (e.g., Nicolet-Barousse_2005, Colussi_2007, Vargas-Poussou_2011, Huang_2018). These data indicate that the variant is very 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: 17699451, 30138938, 15824853, 21415153). Four submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Additionally, another missense variant affecting the same codon, c.947G>T (p.G316V), have been classified as pathogenic/likely pathogenic in Clinvar, reported in both compound heterozygous and homozygous patients with Gitelman Syndrome in the literature (PMIDs: 21415153, 17329572), and functional studies have shown p.G316V causes a severe defect in protein function (PMID: 17329572). Based on the evidence outlined above, the variant was classified as pathogenic.
Institute of Immunology and Genetics Kaiserslautern	RCV002497870	SCV005382182	likely pathogenic	Familial hypokalemia-hypomagnesemia	2024-06-13	criteria provided, single submitter	clinical testing	ACMG Criteria: PM2_P, PM5, PP3, PP2, PM3, PP5, PP4, PP1; Variant was found in heterozygous state together with the heterozygous variant NM_001126108.2:c.533C>T