ClinVar Miner

Submissions for variant NM_001126108.2(SLC12A3):c.2633+1G>A

gnomAD frequency: 0.00001  dbSNP: rs778455414
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001204837 SCV001376062 pathogenic not provided 2023-12-10 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 22 of the SLC12A3 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in SLC12A3 are known to be pathogenic (PMID: 20848653, 22009145, 25841442). This variant is present in population databases (rs778455414, gnomAD 0.002%). Disruption of this splice site has been observed in individuals with Gitelman syndroe (PMID: 24830959). ClinVar contains an entry for this variant (Variation ID: 936104). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
European Hospital Georges Pompidou Genetics Department, Assistance Publique - Hôpitaux de Paris AP-HP RCV001833800 SCV002513842 pathogenic Familial hypokalemia-hypomagnesemia 2022-04-27 criteria provided, single submitter clinical testing ACMG criteria used:PVS1, PS4, PM2, PM3 , PP1, PP3, PP5
Fulgent Genetics, Fulgent Genetics RCV001833800 SCV002786731 pathogenic Familial hypokalemia-hypomagnesemia 2022-01-18 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001833800 SCV003800731 pathogenic Familial hypokalemia-hypomagnesemia 2023-01-11 criteria provided, single submitter clinical testing Variant summary: SLC12A3 c.2660+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes the canonical 5' splicing donor site. However to our knowledge, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 8e-06 in 251044 control chromosomes (gnomAD). c.2660+1G>A has been reported in the literature as a biallelic genotype in multiple individuals affected with Familial Hypokalemia-Hypomagnesemia/Gitelman syndrome (e.g.Tseng_2012, Tavira_2014, Gug_2018, Fujimura_2019, Zhong_2019). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Natera, Inc. RCV001833800 SCV002089377 pathogenic Familial hypokalemia-hypomagnesemia 2017-06-21 no assertion criteria provided clinical testing

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