ClinVar Miner

Submissions for variant NM_001126108.2(SLC12A3):c.1924C>T (p.Arg642Cys)

dbSNP: rs200697179
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001215299 SCV001387036 pathogenic not provided 2024-01-29 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 642 of the SLC12A3 protein (p.Arg642Cys). This variant is present in population databases (rs200697179, gnomAD 0.07%). This missense change has been observed in individual(s) with Gitelman syndrome (PMID: 10561140, 15069170, 16370563, 21051746). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as c.1930C>T. ClinVar contains an entry for this variant (Variation ID: 944812). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This variant disrupts the p.Arg642 amino acid residue in SLC12A3. Other variant(s) that disrupt this residue have been observed in individuals with SLC12A3-related conditions (PMID: 12112667), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
3billion RCV001833878 SCV002521448 pathogenic Familial hypokalemia-hypomagnesemia 2022-05-22 criteria provided, single submitter clinical testing The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.012%). Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.53; 3Cnet: 1.00). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with SLC12A3 related disorder (ClinVar ID: VCV000944812 / PMID: 10561140). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PMID: 10561140, 15069170, 16370563). The variant has been reported to co-segregate with the disease in at least one similarly affected relative/individual in the same family or similarly affected unrelated family (PMID: 15069170). Different missense changes at the same codon (p.Arg642Gly, p.Arg642His) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000319909, VCV000397523). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Fulgent Genetics, Fulgent Genetics RCV001833878 SCV002785567 pathogenic Familial hypokalemia-hypomagnesemia 2022-03-01 criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV001833878 SCV003827919 pathogenic Familial hypokalemia-hypomagnesemia 2022-06-17 criteria provided, single submitter clinical testing
Natera, Inc. RCV001833878 SCV002089360 pathogenic Familial hypokalemia-hypomagnesemia 2020-04-02 no assertion criteria provided clinical testing

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