Submissions for variant NM_001126108.2(SLC12A3):c.965C>T (p.Ala322Val)

gnomAD frequency: 0.00157  dbSNP: rs142679083

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000591358	SCV000704020	uncertain significance	not provided	2016-11-23	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000591358	SCV001029316	likely benign	not provided	2024-01-30	criteria provided, single submitter	clinical testing
Mendelics	RCV000989608	SCV001140112	uncertain significance	Familial hypokalemia-hypomagnesemia	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000989608	SCV001276802	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	RCV000989608	SCV001716396	uncertain significance	Familial hypokalemia-hypomagnesemia	2021-05-18	criteria provided, single submitter	clinical testing
GeneDx	RCV000591358	SCV001874870	uncertain significance	not provided	2023-11-16	criteria provided, single submitter	clinical testing	Reported along with a second variant in the SLC12A3 gene in two patients with Gitelman syndrome in the published literature; however, segregation information was not provided (PMID: 21415153); Reported as a variant of uncertain clinical significance along with two additional SLC12A3 variants in an individual referred from a nephrology clinic; however specific phenotype and segregation information was not provided (PMID: 33226606); Reported as a single heterozygous variant in an individual with salt-wasting congenital adrenal hyperplasia with subsequent hypokalemia; a homozygous pathogenic variant in CYP21A was also identified (PMID: 33763274); 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: 34426522, 33226606, 21415153, 33763274)
European Hospital Georges Pompidou Genetics Department, Assistance Publique - Hôpitaux de Paris AP-HP	RCV000989608	SCV002513851	uncertain significance	Familial hypokalemia-hypomagnesemia	2022-04-27	criteria provided, single submitter	clinical testing	ACMG criteria used:PM1 PM2 BS2, BP2
CeGaT Center for Human Genetics Tuebingen	RCV000591358	SCV004139420	likely benign	not provided	2023-02-01	criteria provided, single submitter	clinical testing	SLC12A3: BP4, BS2
Mayo Clinic Laboratories, Mayo Clinic	RCV000591358	SCV004227588	uncertain significance	not provided	2023-02-13	criteria provided, single submitter	clinical testing	BP4, PM3
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003488715	SCV004241541	likely benign	not specified	2023-12-15	criteria provided, single submitter	clinical testing	Variant summary: SLC12A3 c.965C>T (p.Ala322Val) results in a non-conservative amino acid change located in the Amino acid permease/ SLC12A domain 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 0.0017 in 251454 control chromosomes in the gnomAD database, including 6 homozygotes. c.965C>T has been reported in the literature in individuals affected with Familial Hypokalemia-Hypomagnesemia (Vargas-Poussou_2011). These report(s) do 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: 21415153). Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments. Based on the evidence outlined above, the variant was classified as likely benign.
Ambry Genetics	RCV004024751	SCV004951101	likely benign	Inborn genetic diseases	2022-10-13	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Natera, Inc.	RCV000989608	SCV001458553	benign	Familial hypokalemia-hypomagnesemia	2020-01-09	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003935605	SCV004755786	likely benign	SLC12A3-related disorder	2024-03-14	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).