ClinVar Miner

Submissions for variant NM_001126108.2(SLC12A3):c.1261T>C (p.Cys421Arg)

gnomAD frequency: 0.00001  dbSNP: rs28936387
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001224839 SCV001397062 pathogenic not provided 2023-10-30 criteria provided, single submitter clinical testing This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 421 of the SLC12A3 protein (p.Cys421Arg). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with clinical features consistent with Gitelman syndrome and/or Gitelman syndrome (PMID: 8528245; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 8585). 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.Cys421 amino acid residue in SLC12A3. Other variant(s) that disrupt this residue have been observed in individuals with SLC12A3-related conditions (PMID: 17699451, 21415153, 27454426, 27582097, 30596175), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000009116 SCV000029333 pathogenic Familial hypokalemia-hypomagnesemia 1996-01-01 no assertion criteria provided literature only
Natera, Inc. RCV000009116 SCV002089348 pathogenic Familial hypokalemia-hypomagnesemia 2020-03-15 no assertion criteria provided clinical testing

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