Submissions for variant NM_001126108.2(SLC12A3):c.2555G>A (p.Arg852His)

gnomAD frequency: 0.00001  dbSNP: rs751929135

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001956268	SCV002243436	pathogenic	not provided	2023-12-20	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 861 of the SLC12A3 protein (p.Arg861His). This variant is present in population databases (rs751929135, gnomAD 0.003%). This missense change has been observed in individual(s) with Gitelman syndrome (PMID: 17873326, 31363482, 33348466). 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.Arg852His. ClinVar contains an entry for this variant (Variation ID: 1458237). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SLC12A3 protein function. This variant disrupts the p.Arg861 amino acid residue in SLC12A3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21415153, 23328711, 27582097, 27872838). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003230719	SCV003928940	likely pathogenic	Familial hypokalemia-hypomagnesemia	2023-04-26	criteria provided, single submitter	clinical testing	Variant summary: SLC12A3 c.2582G>A (p.Arg861His) results in a non-conservative amino acid change located in the C-terminal domain (IPR018491) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251076 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2582G>A has been reported in the literature in both compound heterozygous and homozygous individuals affected with Familial Hypokalemia-Hypomagnesemia (e.g., Aoi_2007, Want_2019, Zhang_2020, Mori_2021). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 17873326, 33348466, 31363482, 32542819). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Additionally, different missense variants affecting the same codon, p.R861C and p.R861S, have been reported in association with Gitelman syndrome in HGMD, and p.R861C was classified as pathogenic in ClinVar. Based on the evidence outlined above, the variant was classified as likely pathogenic.