Submissions for variant NM_001126108.2(SLC12A3):c.248G>A (p.Arg83Gln)

gnomAD frequency: 0.00004  dbSNP: rs768527231

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000779192	SCV000915723	likely pathogenic	Familial hypokalemia-hypomagnesemia	2018-09-17	criteria provided, single submitter	clinical testing	The SLC12A3 c.248G>A (p.Arg83Gln) variant has been reported in three studies and found in a total of three individuals with Gitelman syndrome, all in a compound heterozygous state (Vargas-Poussou et al. 2011, Lo et al. 2011, Syren et al. 2011). The p.Arg83Gln variant was absent from 200 control chromosomes and is reported at a frequency of 0.00003 in the total population of the Exome Aggregation Consortium (Vargas-Poussou et al. 2011). Based on the evidence, the p.Arg83Gln variant is 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	RCV001040338	SCV001203903	pathogenic	not provided	2024-03-01	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 83 of the SLC12A3 protein (p.Arg83Gln). This variant is present in population databases (rs768527231, gnomAD 0.03%). This missense change has been observed in individuals with Gitelman syndrome (PMID: 20675610, 21051746, 21415153, 30596175). ClinVar contains an entry for this variant (Variation ID: 632258). 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.Arg83 amino acid residue in SLC12A3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21415153, 27582097). 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.
Johns Hopkins Genomics, Johns Hopkins University	RCV000779192	SCV002051775	likely pathogenic	Familial hypokalemia-hypomagnesemia	2021-12-01	criteria provided, single submitter	clinical testing	SLC12A3 c.248G>A has been identified in multiple individuals with Gitelman syndrome. This variant (rs768527231) is rare (<0.1%) in a large population dataset (gnomAD: 12/282016 total alleles; 0.0043%; no homozygotes) and has been reported in ClinVar (Variation ID: 632258). Three bioinformatic tools queried predict that this substitution would be damaging and the arginine residue at this position is evolutionarily conserved across all species assessed. We consider SLC12A3 c.248G>A to be likely pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000779192	SCV002768933	pathogenic	Familial hypokalemia-hypomagnesemia	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Gitelman syndrome (MIM#263800). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (12 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (8 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated amino acid permease N-terminal domain (DECIPHER). (I) 0703 - Another missense variant comparable to the one identified in this case has moderate previous evidence for pathogenicity. This alternative change (p.(Arg83Trp)) has been reported as likely pathogenic and pathogenic, and observed in multiple individuals with Gitelman syndrome (ClinVar, PMID: 30596175). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as likely pathogenic, and reported in many compound heterozygous individuals with Gitelman syndrome (ClinVar, PMID: 30596175, PMID: 34046503, PMID: 31398183). (SP) 1205 - This variant has been shown to be maternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
GeneDx	RCV001040338	SCV003915148	likely pathogenic	not provided	2022-10-09	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30596175, 31672324, 33807568, 34046503, 21051746, 21415153, 28700713, 31398183, 20675610, 33996672)
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV000779192	SCV005416671	pathogenic	Familial hypokalemia-hypomagnesemia		criteria provided, single submitter	clinical testing	PM2_Supporting+PM5+PP3_Moderate+PM3_VeryStrong+PP4
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	RCV000779192	SCV005420465	likely pathogenic	Familial hypokalemia-hypomagnesemia	2024-10-04	criteria provided, single submitter	research	PM3,PM5,PM2,PP3
Natera, Inc.	RCV000779192	SCV001458481	likely pathogenic	Familial hypokalemia-hypomagnesemia	2020-09-16	no assertion criteria provided	clinical testing