Submissions for variant NM_001126108.2(SLC12A3):c.2549T>C (p.Leu850Pro)

gnomAD frequency: 0.00018  dbSNP: rs121909379

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000805008	SCV000944950	pathogenic	not provided	2024-04-27	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 859 of the SLC12A3 protein (p.Leu859Pro). This variant is present in population databases (rs121909379, gnomAD 0.04%). This missense change has been observed in individual(s) with SLC12A3-related conditions (PMID: 8528245, 19016647, 21415153, 23328711, 27582097). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as p.Leu850Pro. ClinVar contains an entry for this variant (Variation ID: 8584). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SLC12A3 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects SLC12A3 function (PMID: 27582097). For these reasons, this variant has been classified as Pathogenic.
Genome-Nilou Lab	RCV000009115	SCV002055349	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	RCV000009115	SCV002513820	pathogenic	Familial hypokalemia-hypomagnesemia	2022-04-27	criteria provided, single submitter	clinical testing	ACMG criteria used:PS3, PS4, PM2, PM3, PP3, PP5
Fulgent Genetics, Fulgent Genetics	RCV000009115	SCV002811069	pathogenic	Familial hypokalemia-hypomagnesemia	2024-03-25	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002512930	SCV003691407	pathogenic	Inborn genetic diseases	2022-11-14	criteria provided, single submitter	clinical testing	The c.2576T>C (p.L859P) alteration is located in exon 22 (coding exon 22) of the SLC12A3 gene. This alteration results from a T to C substitution at nucleotide position 2576, causing the leucine (L) at amino acid position 859 to be replaced by a proline (P). Based on data from gnomAD, the C allele has an overall frequency of 0.012% (33/282520) total alleles studied. The highest observed frequency was 0.042% (15/35392) of Latino alleles. This variant has been reported in the homozygous state in multiple individuals with Gitelman syndrome and in conjunction with a second variant in SLC12A3 in individuals with Gitelman syndrome (Simon, 1996; Ji, 2008; Vargas-Poussou, 2011; Berry, 2013; Hureaux, 2019). This amino acid position is well conserved in available vertebrate species. Functional assays demonstrate reduced enzyme activity, protein abundance, post-translation modifications and aberrant protein localization in vitro (Valdez-Flores, 2016). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
GeneDx	RCV000805008	SCV003853019	pathogenic	not provided	2023-03-27	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect due to decreased expression and significantly lower activity of the sodium-chloride cotransporter (NCC) compared to wild-type, impaired NCC glycosylation, and disrupted NCC phosphorylation (Valdez-Flores et al., 2016); 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: 8528245, 19016647, 27582097, 31672324, 23328711, 21753071, 31589614, 36314956, 34604727, 35591852, 21415153)
PreventionGenetics, part of Exact Sciences	RCV003421914	SCV004116622	pathogenic	SLC12A3-related disorder	2022-12-21	criteria provided, single submitter	clinical testing	The SLC12A3 c.2576T>C variant is predicted to result in the amino acid substitution p.Leu859Pro. This variant has been reported in the homozygous and compound heterozygous states in several individuals with Gitelman syndrome (reported as L850P in Simon et al. 1996. PubMed ID: 8528245; Supplemental tables in Vargas-Poussou et al. 2011. PubMed ID: 21415153; Berry et al. 2013. PubMed ID: 23328711). Functional studies in HEK293 cells indicated this variant results in significantly decreased NaCl cotransporter activity (Valdez-Flores et al. 2016. PubMed ID: 27582097). This variant is reported in 0.042% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-56928470-T-C). This variant is interpreted as pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000009115	SCV005086311	pathogenic	Familial hypokalemia-hypomagnesemia	2023-07-17	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Gitelman syndrome (MIM#263800). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from leucine to proline. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (33 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (p.(Leu850Ile): 1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated SLC12 family domain (DECIPHER). (I) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. The p.(Leu850Phe) variant has been classified as likely pathogenic by one clinical diagnostic laboratory (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as likely pathogenic and pathogenic by multiple clinical diagnostic laboratories (ClinVar). This variant has also been reported with a second SLC12A3 variant in multiple individuals with a clinical diagnosis of Gitelman syndrome and classified as pathogenic (PMID: 31672324). However, it should be noted that for the majority of these individuals, the phasing of the variants is unknown (PMID: 31672324). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
OMIM	RCV000009115	SCV000029332	pathogenic	Familial hypokalemia-hypomagnesemia	1996-01-01	no assertion criteria provided	literature only
Baylor Genetics	RCV000009115	SCV000245538	pathogenic	Familial hypokalemia-hypomagnesemia	2022-01-29	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000009115	SCV001462626	pathogenic	Familial hypokalemia-hypomagnesemia	2020-09-16	no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000805008	SCV001930377	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000805008	SCV001954250	likely pathogenic	not provided		no assertion criteria provided	clinical testing