Submissions for variant NM_001126108.2(SLC12A3):c.539C>A (p.Thr180Lys)

gnomAD frequency: 0.00003  dbSNP: rs146158333

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000803323	SCV000943187	pathogenic	not provided	2024-01-15	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with lysine, which is basic and polar, at codon 180 of the SLC12A3 protein (p.Thr180Lys). This variant is present in population databases (rs146158333, gnomAD 0.4%). This missense change has been observed in individual(s) with Gitelman syndrome (PMID: 10616841, 21628937, 21757836, 26041598). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 648571). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SLC12A3 protein function. For these reasons, this variant has been classified as Pathogenic.
Illumina Laboratory Services, Illumina	RCV001115368	SCV001273339	uncertain significance	Familial hypokalemia-hypomagnesemia	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Genome-Nilou Lab	RCV001115368	SCV002055285	likely pathogenic	Familial hypokalemia-hypomagnesemia	2021-07-15	criteria provided, single submitter	clinical testing
3billion	RCV001115368	SCV002521201	likely pathogenic	Familial hypokalemia-hypomagnesemia	2022-05-22	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.025%). Missense changes are a common disease-causing mechanism. Same nucleotide change resulting in same amino acid change has been previously reported to be associated with SLC12A3 related disorder (ClinVar ID: VCV000648571 / PMID: 10616841). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 26041598) and to co-segregate with the disease in at least one similarly affected relative/individual in the same family or similarly affected unrelated family (PMID:10616841). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.
Natera, Inc.	RCV001115368	SCV002089329	pathogenic	Familial hypokalemia-hypomagnesemia	2021-02-23	no assertion criteria provided	clinical testing