Submissions for variant NM_001126108.2(SLC12A3):c.434G>A (p.Arg145His)

gnomAD frequency: 0.00004  dbSNP: rs374324018

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000778471	SCV000914726	likely pathogenic	Familial hypokalemia-hypomagnesemia	2018-10-22	criteria provided, single submitter	clinical testing	The SLC12A3 c.434G>A (p.Arg145His) variant has been reported in two studies and is found in a total of four probands. In one proband with Gitelman syndrome, the p.Arg145His variant was detected in a homozygous state, along with another missense variant in a heterozygous state (Fava et al. 2007). In three probands with hypokalemic salt-losing tubulopathy, the p.Arg145His variant was detected in a compound heterozygous state with a second missense variant (Zhang et al. 2013). The p.Arg145His variant was absent from 50 controls and is reported at a frequency of 0.0004711 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the evidence, the p.Arg145His variant is therefore classified as likely pathogenic for Gitelman syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001379908	SCV001577806	pathogenic	not provided	2023-12-11	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 145 of the SLC12A3 protein (p.Arg145His). This variant is present in population databases (rs374324018, gnomAD 0.03%). This missense change has been observed in individuals with clinical features of Gitelman syndrome (PMID: 17654016, 22934535, 31672324). ClinVar contains an entry for this variant (Variation ID: 631752). 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.Arg145 amino acid residue in SLC12A3. Other variant(s) that disrupt this residue have been observed in individuals with SLC12A3-related conditions (PMID: 17329572, 31672324), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001379908	SCV001985409	uncertain significance	not provided	2019-04-17	criteria provided, single submitter	clinical testing	Observed in apparent homozygous state in a patient with Gitelman syndrome in published literature (Fava et al., 2007), however, this individual was also heterozygous for another SLC12A3 variant; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 17654016, 31672324)
Genome-Nilou Lab	RCV000778471	SCV002055284	likely pathogenic	Familial hypokalemia-hypomagnesemia	2021-07-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002536732	SCV003607866	pathogenic	Inborn genetic diseases	2022-09-19	criteria provided, single submitter	clinical testing	The c.434G>A (p.R145H) alteration is located in exon 3 (coding exon 3) of the SLC12A3 gene. This alteration results from a G to A substitution at nucleotide position 434, causing the arginine (R) at amino acid position 145 to be replaced by a histidine (H). Based on data from gnomAD, the A allele has an overall frequency of 0.013% (38/282192) total alleles studied. The highest observed frequency was 0.026% (33/128856) of European (non-Finnish) alleles. This variant has been identified homozygous or in conjunction with a second ACADVL variant in multiple individuals with clinical features of Gitelman syndrome (Fava, 2007; Zhang, 2013; Hureaux, 2019; Pinto E Vairo, 2021). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
Natera, Inc.	RCV000778471	SCV002089324	likely pathogenic	Familial hypokalemia-hypomagnesemia	2021-01-25	no assertion criteria provided	clinical testing