Submissions for variant NM_001126108.2(SLC12A3):c.2920G>A (p.Val974Ile)

gnomAD frequency: 0.00009  dbSNP: rs373092349

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000394498	SCV000398145	uncertain significance	Familial hypokalemia-hypomagnesemia	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002522873	SCV003264211	uncertain significance	not provided	2022-07-31	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 983 of the SLC12A3 protein (p.Val983Ile). This variant is present in population databases (rs373092349, gnomAD 0.05%). This missense change has been observed in individual(s) with Gitelman syndrome (PMID: 23328711). ClinVar contains an entry for this variant (Variation ID: 319920). 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 not expected to disrupt SLC12A3 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003323514	SCV004028608	uncertain significance	not specified	2023-07-10	criteria provided, single submitter	clinical testing	Variant summary: SLC12A3 c.2947G>A (p.Val983Ile) results in a conservative amino acid change located in the SLC12A transporter, C-terminal domain (IPR018491) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-05 in 251444 control chromosomes. c.2947G>A has been reported in the literature as a compound heterozygous genotype (although phase was not determined/specified) in an individual affected with Hypokalemia-Hypomagnesemia (Gitelman syndrome) (Berry_2013). This report does not provide unequivocal conclusions about association of the variant with Familial Hypokalemia-Hypomagnesemia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 23328711). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and both classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV003409501	SCV004114423	uncertain significance	SLC12A3-related disorder	2023-10-06	criteria provided, single submitter	clinical testing	The SLC12A3 c.2947G>A variant is predicted to result in the amino acid substitution p.Val983Ile. This variant was reported along with a second SLC12A3 variant (c.1258G>A, p.Ala420Thr) in an individual with Gitelman syndrome (Berry et al 2013. PubMed ID: 23328711). This variant is reported in 0.044% of alleles in individuals of European (Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-56938370-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.