ClinVar Miner

Submissions for variant NM_001126108.2(SLC12A3):c.2546T>A (p.Leu849His)

gnomAD frequency: 0.00001  dbSNP: rs185927948
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000713330 SCV000843927 pathogenic not provided 2016-04-01 criteria provided, single submitter clinical testing
Illumina Laboratory Services, Illumina RCV000490297 SCV000915725 pathogenic Familial hypokalemia-hypomagnesemia 2017-04-28 criteria provided, single submitter clinical testing Across a selection of the available literature, the SLC12A3 c.2573T>A (p.Leu858His) variant, also known as c.2579T>A (p.Leu849His), has been reported in 10 studies and is found in a total of 13 patients with Gitelman syndrome, including two in a homozygous state, eight in a compound heterozygous state, and three in a heterozygous state where the second variant could not be identified (Monkawa et al. 2000; Fukuyama et al. 2003; Maki et al. 2004; Aoi et al. 2007; Tsutsui et al. 2011; Yagi et al. 2011; Imashuku et al. 2012; Ishimori et al. 2013; Miao et al. 2016; Mizokami et al. 2016). The p.Leu858His variant was absent from 400 control chromosomes in some studies (Monkawa et al. 2000; Fukuyama et al. 2003; Maki et al. 2004), however, the variant was detected in 47 out of 1852 healthy Japanese subjects in a heterozygous state (Tago et al. 2004) and is reported at a frequency of 0.01442 in the Japanese in Tokyo, Japan cohort of the 1000 Genomes Project. While this frequency is high, it is in alignment with the increased prevalence of Gitelman syndrome in Japan. In functional studies, sodium uptake of the p.Leu858His variant protein was found to be significantly reduced when expressed and evaluated in CHO cells, indicating that the p.Leu858His variant leads to loss of function (Naraba et al. 2005). Based on the evidence, the p.Leu858His 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 RCV000713330 SCV000940176 pathogenic not provided 2023-12-14 criteria provided, single submitter clinical testing This sequence change replaces leucine, which is neutral and non-polar, with histidine, which is basic and polar, at codon 858 of the SLC12A3 protein (p.Leu858His). This variant is present in population databases (rs185927948, gnomAD 0.09%). This missense change has been observed in individual(s) with SLC12A3-related conditions (PMID: 15069170, 21628937, 21757836, 26041598, 26770037). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as p.Leu849His. ClinVar contains an entry for this variant (Variation ID: 225470). 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: 16471174). For these reasons, this variant has been classified as Pathogenic.
3billion RCV000490297 SCV002012228 pathogenic Familial hypokalemia-hypomagnesemia 2021-10-02 criteria provided, single submitter clinical testing The variant has been reported to be in trans with a pathogenic variant as compound heterozygous in at least 2 similarly affected unrelated individuals (PMID: 21628937, 26770037, PM3_S). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 16471174, PS3) It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0000597, PM2). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.783, PP3). Patient's phenotype is considered compatible with Gitelman syndrome (3billion dataset, PP4). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Genome-Nilou Lab RCV000490297 SCV002055314 pathogenic Familial hypokalemia-hypomagnesemia 2021-07-15 criteria provided, single submitter clinical testing
GeneDx RCV000713330 SCV002520209 pathogenic not provided 2021-11-18 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect as p.(L858H) results in loss-of-function (Naraba et al., 2005); 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: 17873326, 33163079, 27173320, 26770037, 22802996, 23756661, 10616841, 15198479, 15069170, 21757836, 19489442, 31105122, 33328404, 21628937, 26041598, 33348466, 32884933, 30596175, 16471174)
Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center RCV000490297 SCV000267501 uncertain significance Familial hypokalemia-hypomagnesemia 2016-03-18 flagged submission reference population
Natera, Inc. RCV000490297 SCV001462625 pathogenic Familial hypokalemia-hypomagnesemia 2020-09-16 no assertion criteria provided clinical testing

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