Submissions for variant NM_001126108.2(SLC12A3):c.1732G>A (p.Val578Met)

gnomAD frequency: 0.00025  dbSNP: rs139329616

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	RCV000279337	SCV000267500	uncertain significance	Familial hypokalemia-hypomagnesemia	2016-03-18	criteria provided, single submitter	reference population
Illumina Laboratory Services, Illumina	RCV000279337	SCV000398120	uncertain significance	Familial hypokalemia-hypomagnesemia	2017-04-27	criteria provided, single submitter	clinical testing	The SLC12A3 c.1732G>A (p.Val578Met) missense variant has been reported in four studies in which it is found in three patients with Gitelman syndrome in a compound heterozygous state, and in a heterozygous state in one patient in whom a second variant was not identified (Monkawa et al. 2000; Kumagai et al. 2010; Nozu et al. 2010; Takahashi et al. 2012). One of the patients who was compound heterozygous was found to carry the p.Val578Met variant and a known pathogenic missense variant on the same allele, precluding the analysis of the p.Val578Met variant's pathogenicity in this individual (Monkawa et al. 2000). The p.Val578Met variant was absent from 150 controls and is reported at a frequency of 0.00751 in the East Asian population of the Exome Aggregation Consortium. The evidence for this variant is limited. The p.Val578Met variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for Gitelman syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae	RCV000901287	SCV001045651	likely benign	not provided	2024-01-25	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000279337	SCV002055297	uncertain significance	Familial hypokalemia-hypomagnesemia	2021-07-15	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003417765	SCV004116689	uncertain significance	SLC12A3-related condition	2023-03-15	criteria provided, single submitter	clinical testing	The SLC12A3 c.1732G>A variant is predicted to result in the amino acid substitution p.Val578Met. This variant has been observed in the heterozygous and also the compound heterozygous state in several individuals with Gitelman syndrome (Monkawa et al. 2000. PubMed ID: 10616841; Nozu et al. 2010. PubMed ID: 20810575; Takahashi et al. 2012. PubMed ID: 22484642; Fujimura et al 2018. PubMed ID: 30596175; Table S7 in Kondo A et al 2021. PubMed ID: 34373523). However, in one of the compound heterozygous individuals the c.1732G>A (p.Val578Met) variant also occurred in cis with a SLC12A3 frameshift variant (Reported as c.2543_2544del in Monkawa et al. 2000. PubMed ID: 10616841). This c.1732G>A was also detected with this same frameshift variant in two additional individuals and phase was not determined, but these variants may represent a haplotype allele in certain populations (Reported as c.2537_2538del in Mori T et al 2020. PubMed ID: 33348466 and Miya A. et al. 2019. Medicine. 98:e16408). This variant has also been reported in a multigenerational family with one individual affected with Gitelman Syndrome; however, it was also detected in the compound heterozygous state in an asymptomatic individual (Ishikawa et al. 2020. PubMed ID: 32884933). This variant is reported in 171 of ~283,000 alleles in gnomAD with a frequency of 0.80% in individuals of East Asian descent (http://gnomad.broadinstitute.org/variant/16-56918023-G-A). This variant has conflicting interpretations of likely benign and uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/225469/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.