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

gnomAD frequency: 0.00014  dbSNP: rs140012781

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000681948	SCV000565567	likely pathogenic	not provided	2023-05-31	criteria provided, single submitter	clinical testing	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: 22169961, 11940055, 17654016, 19349556, 11168953, 15976513, 21753071, 22009145, 28947054, 21415153, 33585337, 31672324, 32129221, 34426522, 35753512, 35327948, 25990047, 37078890)
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 Laboratory Services, 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	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 643 of the SLC12A3 protein (p.Pro643Leu). This variant is present in population databases (rs140012781, gnomAD 0.2%). This missense change has been observed in individuals with Gitelman syndrome (PMID: 11168953, 11940055, 17654016, 21753071, 22169961). ClinVar contains an entry for this variant (Variation ID: 417863). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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.
Athena Diagnostics Inc	RCV000681948	SCV001879512	pathogenic	not provided	2020-12-22	criteria provided, single submitter	clinical testing	This variant is statistically more frequent in affected individuals than in the general population and/or healthy controls and therefore is consistent with pathogenicity (http://gnomad.broadinstitute.org). In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. Computational tools predict that this variant is damaging.
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000477915	SCV001976816	pathogenic	Familial hypokalemia-hypomagnesemia	2021-10-05	criteria provided, single submitter	clinical testing	PM2, PP2, PP3, PP5
Genome-Nilou Lab	RCV000477915	SCV002055341	likely pathogenic	Familial hypokalemia-hypomagnesemia	2021-07-15	criteria provided, single submitter	clinical testing
European Hospital Georges Pompidou Genetics Department, Assistance Publique - Hôpitaux de Paris AP-HP	RCV000477915	SCV002513813	likely pathogenic	Familial hypokalemia-hypomagnesemia	2022-04-27	criteria provided, single submitter	clinical testing	ACMG criteria used:PS4, PM1, PM2, PM3, PP3, PP5
Fulgent Genetics, Fulgent Genetics	RCV000477915	SCV002780754	pathogenic	Familial hypokalemia-hypomagnesemia	2022-03-26	criteria provided, single submitter	clinical testing
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)
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000681948	SCV001928624	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000681948	SCV001957402	likely pathogenic	not provided		no assertion criteria provided	clinical testing