ClinVar Miner

Submissions for variant NM_001126108.2(SLC12A3):c.1928C>T (p.Pro643Leu) (rs140012781)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000681948 SCV000565567 uncertain significance not provided 2017-11-28 criteria provided, single submitter clinical testing The P643L variant in the SLC12A3 gene has been reported previously in association with Gitelman syndrome in affected individuals who also harbored an additional variant in the SLC12A3 gene; however, familial segregation studies were not performed in most cases (Cruz et al., 2001; Pantanetti et al., 2002; Fava et al., 2007). Although not observed in the homozygous state, the P643L variant is observed in 18/10146 (0.177%) alleles from individuals of Ashkenazi Jewish background and in 48/275988 (0.017%) global alleles in large population cohorts (Lek et al., 2016). The P643L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. We interpret P643L as a variant of uncertain significance.
Center of Genomic medicine, Geneva,University Hospital of Geneva RCV000477915 SCV000897978 pathogenic Familial hypokalemia-hypomagnesemia 2018-05-30 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000477915 SCV000914249 pathogenic Familial hypokalemia-hypomagnesemia 2019-04-08 criteria provided, single submitter clinical testing Across a selection of the available literature, the SLC12A3 c.1928C>T (p.Pro643Leu) missense variant has been reported in at least 20 unrelated individuals affected with Gitelman syndrome, including in a homozygous state in three and in a compound heterozygous state in 17 (Cruz et al. 2001; Pantanetti et al. 2002; Talaulikar and Falk 2005; Vargas-Poussou et al. 2011; Balavoine et al. 2011; Glaudemans et al. 2012; Nakhoul et al. 2012; Zahed et al. 2017). Control data are unavailable for this variant, which is reported at a frequency of 0.001774 in the Ashkenazi Jewish population of the Genome Aggregation Database. Based on the collective evidence, the p.Pro643Leu variant is classified as pathogenic for Gitelman syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV000681948 SCV001576570 likely pathogenic not provided 2020-10-27 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 643 of the SLC12A3 protein (p.Pro643Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs140012781, ExAC 0.03%). This variant has been observed in individual(s) with Gitelman's syndrome (PMID: 11168953, 11940055, 22169961, 21753071, 17654016). ClinVar contains an entry for this variant (Variation ID: 417863). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Division of Human Genetics,Children's Hospital of Philadelphia RCV000477915 SCV000536716 pathogenic Familial hypokalemia-hypomagnesemia 2015-09-23 no assertion criteria provided research
Gharavi Laboratory,Columbia University RCV000681948 SCV000809436 pathogenic not provided 2018-09-16 no assertion criteria provided research
Sydney Genome Diagnostics,Children's Hospital Westmead RCV001328101 SCV001449422 likely pathogenic Familial hypokalemia-hypomagnesemia; Bartter syndrome 2018-10-24 no assertion criteria provided clinical testing This patient is heterozygous for a likely pathogenic variant, c.1928C>T p.(Pro643Leu), in the SLC12A3 gene. This variant (dbSNP: rs140012787) has been reported in the ExAC database (http://exac.broadinstitute.org/) with a very low allele frequency of 0.018% (22 out of 119660 alleles). This variant has been previously reported in trans with other SLC12A3 variants in patients with Gitelman syndrome in the literature (Vargas-Poussou et al 2011 J Am Soc Nephrol 22:693-703). In addition, this variant has been reported in cis with SLC12A3 p.(Pro548Leu), and in trans with SLC12A3 p.(Gly439Ser), in a patient with remarkably severe Gitelman syndrome (Roser et al 2009 Hypertension 53:893-897)

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