Submissions for variant NM_001126108.2(SLC12A3):c.1670-191C>T

gnomAD frequency: 0.00003  dbSNP: rs374182921

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000823626	SCV000964491	pathogenic	not provided	2025-01-15	criteria provided, single submitter	clinical testing	This sequence change falls in intron 13 of the SLC12A3 gene. It does not directly change the encoded amino acid sequence of the SLC12A3 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or altered protein product. This variant is present in population databases (rs374182921, gnomAD 0.06%). This variant has been observed in individual(s) with SLC12A3-related conditions (PMID: 19668106, 21051746). 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. ClinVar contains an entry for this variant (Variation ID: 665361). Studies have shown that this variant results in activation of a cryptic splice site, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 19668106). For these reasons, this variant has been classified as Pathogenic.
Centogene AG - the Rare Disease Company	RCV001251115	SCV001426480	pathogenic	Familial hypokalemia-hypomagnesemia		criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV001251115	SCV001752826	pathogenic	Familial hypokalemia-hypomagnesemia	2022-05-02	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001251115	SCV002020627	pathogenic	Familial hypokalemia-hypomagnesemia	2019-11-14	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001251115	SCV002055336	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	RCV001251115	SCV002513836	pathogenic	Familial hypokalemia-hypomagnesemia	2022-04-27	criteria provided, single submitter	clinical testing	ACMG criteria used:PS4 PS3, PM2, PM3, PP3, PP5
GeneDx	RCV000823626	SCV002758879	pathogenic	not provided	2022-05-31	criteria provided, single submitter	clinical testing	Published functional studies demonstrated that this variant activates a cryptic splice site (Lo et al., 2011; Nozu et al., 2009); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis, which includes splice predictors and evolutionary conservation, suggests this variant may impact gene splicing.; This variant is associated with the following publications: (PMID: 30596175, 32860008, 19668106, 21051746)
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV001251115	SCV004807891	pathogenic	Familial hypokalemia-hypomagnesemia	2025-01-04	criteria provided, single submitter	clinical testing
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	RCV001251115	SCV005420466	pathogenic	Familial hypokalemia-hypomagnesemia	2024-10-04	criteria provided, single submitter	research	PS3, PM2, PM3(strong), PP3,PP1
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001251115	SCV005423387	pathogenic	Familial hypokalemia-hypomagnesemia	2024-10-04	criteria provided, single submitter	clinical testing	Variant summary: SLC12A3 c.1670-191C>T is located at a position not widely known to affect splicing. Computational tools predict a significant impact on normal splicing: Three predict the variant creates a cryptic 5' donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing, resulting in the inclusing of a pseudoexon by activating a cryptic splice donor site (Viering_2023). The variant allele was found at a frequency of 3.2e-05 in 31384 control chromosomes (gnomAD). c.1670-191C>T has been reported in the literature in multiple individuals affected with Familial Hypokalemia-Hypomagnesemia (e.g. Viering_2023). These data indicate that the variant is very likely to be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 36302598). ClinVar contains an entry for this variant (Variation ID: 665361). Based on the evidence outlined above, the variant was classified as pathogenic.
Natera, Inc.	RCV001251115	SCV001462612	pathogenic	Familial hypokalemia-hypomagnesemia	2020-09-16	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003928288	SCV004755051	pathogenic	SLC12A3-related disorder	2024-07-30	no assertion criteria provided	clinical testing	The SLC12A3 c.1670-191C>T variant is predicted to interfere with splicing. This variant has been reported in the compound heterozygous and homozygous state in several individuals with Gitelman syndrome (Nozu et al. 2009. PubMed ID: 19668106; Lo et al. 2010. PubMed ID: 21051746; Supp. Table 1 in Fujimura et al. 2018. PubMed ID: 30596175). Analysis of mRNA from patients indicates that this variant results in activation of a cryptic donor site and a 238-bp insertion (Nozu et al. 2009. PubMed ID: 19668106; Lo et al. 2010. PubMed ID: 21051746). This variant is reported in 0.064% of alleles in individuals of East Asian descent in gnomAD. This variant is interpreted as pathogenic.