Submissions for variant NM_001126108.2(SLC12A3):c.1258G>A (p.Ala420Thr)

gnomAD frequency: 0.00001  dbSNP: rs137970015

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001797016	SCV002038533	uncertain significance	Familial hypokalemia-hypomagnesemia	2021-06-29	criteria provided, single submitter	clinical testing	The SLC12A3 c.1258G>A (p.Ala420Thr) variant is a missense variant that has been reported in a presumed compound heterozygous state with the p.Val983Ile variant, which is also known as c.2920G>A (p.Val974Ile), in one individual with Gitelman syndrome who experienced onset of symptoms at 33 years of age (Berry et al. 2013). This variant is reported at a frequency of 0.000201 in the East Asian population of the Genome Aggregation Database (v2.1.1). In silico tools are not consistent in the predicted effect of this variant on protein function. Based on the limited evidence available, the p.Ala420Thr variant is classified as a variant of uncertain significance for Gitelman syndrome.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002541301	SCV003264210	uncertain significance	not provided	2022-07-31	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 420 of the SLC12A3 protein (p.Ala420Thr). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with SCL12A3-related conditions (PMID: 23328711). ClinVar contains an entry for this variant (Variation ID: 1328532). 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	RCV003323933	SCV004028611	uncertain significance	not specified	2023-07-10	criteria provided, single submitter	clinical testing	Variant summary: SLC12A3 c.1258G>A (p.Ala420Thr) results in a non-conservative amino acid change located in the amino acid permease/SLC12 domain (IPR004841) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 250618 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1258G>A has been reported in the literature in the compound heterozygous state (although phase was not tested/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 have 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	RCV003416460	SCV004118160	uncertain significance	SLC12A3-related disorder	2023-10-06	criteria provided, single submitter	clinical testing	The SLC12A3 c.1258G>A variant is predicted to result in the amino acid substitution p.Ala420Thr. This variant was reported along with a second SLC12A3 variant (c.2947G>A, p.Val983Ile) in an individual with Gitelman syndrome (Berry et al 2013. PubMed ID: 23328711). This variant is reported in 0.020% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-56913062-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.