ClinVar Miner

Submissions for variant NM_001126108.2(SLC12A3):c.2546T>A (p.Leu849His) (rs185927948)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Soonchunhyang University Bucheon Hospital,Soonchunhyang University Medical Center RCV000490297 SCV000267501 uncertain significance Familial hypokalemia-hypomagnesemia 2016-03-18 criteria provided, single submitter reference population
Athena Diagnostics Inc RCV000713330 SCV000843927 pathogenic not provided 2016-04-01 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,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 2020-10-08 criteria provided, single submitter clinical testing This sequence change replaces leucine with histidine at codon 858 of the SLC12A3 protein (p.Leu858His). The leucine residue is moderately conserved and there is a moderate physicochemical difference between leucine and histidine. This variant is present in population databases (rs185927948, ExAC 0.1%). This variant has been observed in several individuals and families with SLC12A3-related conditions (PMID: 21628937, 26041598, 21757836, 15069170, 26770037). This variant has been also observed on the opposite chromosome (in trans) from other pathogenic variants in individuals affected with SLC12A3-related conditions (PMID: 15069170, 21628937). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. This variant is also know as p.Leu849His. ClinVar contains an entry for this variant (Variation ID: 225470). Experimental studies have shown that this missense change has a deleterious effect on protein function (PMID: 16471174). For these reasons, this variant has been classified as Pathogenic.
Natera, Inc. RCV000490297 SCV001462625 pathogenic Familial hypokalemia-hypomagnesemia 2020-09-16 no assertion criteria provided clinical testing

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