rs185927948
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PM5PP5_Very_Strong
The NM_001126108.2(SLC12A3):c.2546T>A(p.Leu849His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000187 in 1,613,866 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L849F) has been classified as Likely pathogenic.
Frequency
Consequence
NM_001126108.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SLC12A3 | NM_001126108.2 | c.2546T>A | p.Leu849His | missense_variant | 22/26 | ENST00000563236.6 | |
SLC12A3 | NM_000339.3 | c.2573T>A | p.Leu858His | missense_variant | 22/26 | ||
SLC12A3 | NM_001126107.2 | c.2570T>A | p.Leu857His | missense_variant | 22/26 | ||
SLC12A3 | NM_001410896.1 | c.2543T>A | p.Leu848His | missense_variant | 22/26 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SLC12A3 | ENST00000563236.6 | c.2546T>A | p.Leu849His | missense_variant | 22/26 | 1 | NM_001126108.2 | A1 | |
SLC12A3 | ENST00000438926.6 | c.2573T>A | p.Leu858His | missense_variant | 22/26 | 1 | A1 | ||
SLC12A3 | ENST00000566786.5 | c.2570T>A | p.Leu857His | missense_variant | 22/26 | 1 | P4 | ||
SLC12A3 | ENST00000262502.5 | c.2543T>A | p.Leu848His | missense_variant | 22/26 | 5 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000657 AC: 10AN: 152130Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000598 AC: 15AN: 251000Hom.: 0 AF XY: 0.0000516 AC XY: 7AN XY: 135634
GnomAD4 exome AF: 0.000199 AC: 291AN: 1461618Hom.: 1 Cov.: 31 AF XY: 0.000188 AC XY: 137AN XY: 727056
GnomAD4 genome ? AF: 0.0000657 AC: 10AN: 152248Hom.: 0 Cov.: 31 AF XY: 0.0000806 AC XY: 6AN XY: 74436
ClinVar
Submissions by phenotype
Familial hypokalemia-hypomagnesemia Pathogenic:4Uncertain:1
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Oct 02, 2021 | 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. - |
Uncertain significance, flagged submission | reference population | Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center | Mar 18, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 28, 2017 | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 15, 2021 | - - |
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 18, 2021 | 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) - |
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Apr 01, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 14, 2023 | 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at