Submissions for variant NM_001126108.2(SLC12A3):c.1964G>A (p.Arg655His)

gnomAD frequency: 0.00011  dbSNP: rs121909380

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics Inc	RCV000518052	SCV000615286	likely pathogenic	not provided	2017-02-09	criteria provided, single submitter	clinical testing
GeneDx	RCV000518052	SCV000617312	pathogenic	not provided	2023-10-30	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 8528245, 11168953, 22934535, 26990548, 17329572, 12590198, 8900229, 28469853, 12112667, 34426522, 24776766, 22009145, 19207868, 31398183, 33996672, 31672324, 33226606, 33532864, Guven[CaseReport]2021, 35591852, 28700713)
Invitae	RCV000518052	SCV000952334	pathogenic	not provided	2024-01-18	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 655 of the SLC12A3 protein (p.Arg655His). This variant is present in population databases (rs121909380, gnomAD 0.02%). This missense change has been observed in individuals with Gitelman syndrome (PMID: 11168953, 22009145, 22934535, 24776766). ClinVar contains an entry for this variant (Variation ID: 8588). 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.Arg655 amino acid residue in SLC12A3. Other variant(s) that disrupt this residue have been observed in individuals with SLC12A3-related conditions (PMID: 9734597, 11168953, 22214629), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Molecular Biology Laboratory, Fundació Puigvert	RCV000009119	SCV001425257	likely pathogenic	Familial hypokalemia-hypomagnesemia	2020-02-01	criteria provided, single submitter	research
Revvity Omics, Revvity	RCV000009119	SCV002020625	pathogenic	Familial hypokalemia-hypomagnesemia	2021-03-17	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000009119	SCV002055344	likely pathogenic	Familial hypokalemia-hypomagnesemia	2021-07-15	criteria provided, single submitter	clinical testing
European Hospital Georges Pompidou Genetics Department, Assistance Publique - Hôpitaux de Paris AP-HP	RCV000009119	SCV002513814	likely pathogenic	Familial hypokalemia-hypomagnesemia	2022-04-27	criteria provided, single submitter	clinical testing	ACMG criteria used:PS4, PM1, PM2, PM5, PP3, PP5
Fulgent Genetics, Fulgent Genetics	RCV000009119	SCV002815025	pathogenic	Familial hypokalemia-hypomagnesemia	2022-04-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000009119	SCV002819887	pathogenic	Familial hypokalemia-hypomagnesemia	2022-12-29	criteria provided, single submitter	clinical testing	Variant summary: SLC12A3 c.1964G>A (p.Arg655His) results in a non-conservative amino acid change located in the SLC12A transporter, C-terminal domain (IPR018491) of the encoded protein sequence. Five 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-05 in 251024 control chromosomes. This frequency does not allow conclusions about variant significance. c.1964G>A has been reported in the literature in multiple individuals affected with Familial Hypokalemia-Hypomagnesemia, Gitelman syndrome (GS) (example, PMID: 33532864, 22009145, 19207868, 17329572, 32542819). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 (P/LP, n=7; VUS, n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM	RCV000009119	SCV000029336	pathogenic	Familial hypokalemia-hypomagnesemia	1996-01-01	no assertion criteria provided	literature only
Sydney Genome Diagnostics, Children's Hospital Westmead	RCV001328221	SCV001449435	uncertain significance	Familial hypokalemia-hypomagnesemia; Bartter syndrome	2018-02-02	no assertion criteria provided	clinical testing	This individual is heterozygous for a known pathogenic variant, c.2883+1G>T, in the SLC12A3 gene. The c.2883+1G>T variant (dbSNP: rs199974259) has been reported in the gnomAD browser with a low allelic frequency of 0.02% (62 out of 276,340 alleles, http://gnomad.broadinstitute.org). This variant is predicted to abolish the consensus splice donor site at c.2883, resulting in the skipping of exon 24. This splice site variant has been previously reported in numerous patients with Gitelman syndrome in the literature (Vargas-Poussou et al 2011 J Am Soc Nephrol 22:693-703; Glaudemans et al 2012 Eur J Hum Genet 20:263-270). This variant is considered to be pathogenic according to the ACMG guidelines.