ClinVar Miner

Submissions for variant NM_001126108.2(SLC12A3):c.363G>C (p.Glu121Asp) (rs146632606)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000607947 SCV000713176 uncertain significance not specified 2018-12-26 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The p.Glu121Asp variant in SLC12A3 has been reported in 3 individuals with autosomal recessive Gitelman syndrome, at least two of whom carried a second disease-causing SLC12A3 variant (Glaudemans, 2012, Berry 2013). In vitro functional studies provide som e evidence that the p.Glu121Asp variant may impact protein function (Glaudemans, 2012). However, these types of assays may not accurately represent biological f unction. This variant has also been identified in 0.16% (209/128370) of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinst Although this variant has been seen in the general population, its f requency is not high enough to rule out a pathogenic role. In summary, while the re is some suspicion for a pathogenic role, the clinical significance of the p.G lu121Asp variant is uncertain. ACMG/AMP Criteria applied: PM3_Strong, PS3_Suppor ting.
Illumina Clinical Services Laboratory,Illumina RCV000778470 SCV000914725 likely pathogenic Familial hypokalemia-hypomagnesemia 2019-01-09 criteria provided, single submitter clinical testing The SLC12A3 c.363G>C (p.Glu121Asp) variant has been reported in two studies and is found in a total of three probands with Gitelman syndrome in a compound heterozygous state (Glaudemans et al. 2012; Berry et al. 2013). Control data are unavailable for this variant, which is reported at a frequency of 0.00132 in the European (non-Finnish) population of the Exome Aggregation Consortium. Functional studies in Xenopus oocytes demonstrated proper localization but sodium uptake was significantly reduced compared to wild type (Glaudemans et al. 2012). Based on the evidence, the p.Glu121Asp variant is classified as likely pathogenic for Gitelman syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Gharavi Laboratory,Columbia University RCV000681735 SCV000809190 likely pathogenic not provided 2018-09-16 no assertion criteria provided research
Natera, Inc. RCV000778470 SCV001458483 uncertain significance Familial hypokalemia-hypomagnesemia 2020-09-16 no assertion criteria provided clinical testing

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