ClinVar Miner

Submissions for variant NM_001126108.2(SLC12A3):c.404G>A (p.Arg135His)

dbSNP: rs769047841
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Laboratory Services, Illumina RCV000778908 SCV000915316 uncertain significance Familial hypokalemia-hypomagnesemia 2017-05-18 criteria provided, single submitter clinical testing The SLC12A3 c.404G>A (p.Arg135His) missense variant has been reported in one study and is found in one individual with Gitelman syndrome in a compound heterozygous state along with another missense variant (Urbanová et al. 2011). This individual also carried two known polymorphisms in the SLC12A3 gene. The p.Arg135His variant was absent from 200 control chromosomes and is reported at a frequency of 0.00005 in the European (non-Finnish) population of the Exome Aggregation Consortium. Urbanová et al. (2011) state that the p.Arg135 residue is highly conserved across multiple species. The evidence for this variant is limited. The p.Arg135His variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for Gitelman syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Fulgent Genetics, Fulgent Genetics RCV000778908 SCV002779270 uncertain significance Familial hypokalemia-hypomagnesemia 2022-04-22 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV002535643 SCV003443523 likely pathogenic not provided 2024-01-11 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 135 of the SLC12A3 protein (p.Arg135His). This variant is present in population databases (rs769047841, gnomAD 0.007%). This missense change has been observed in individual(s) with clinical features of Gitelman syndrome (PMID: 21631963). ClinVar contains an entry for this variant (Variation ID: 632060). 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%. This variant disrupts the p.Arg135 amino acid residue in SLC12A3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21415153, 31672324). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Breakthrough Genomics, Breakthrough Genomics RCV002535643 SCV005194402 uncertain significance not provided criteria provided, single submitter not provided

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