rs759377924

Positions:

• chr16-56879207-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_001126108.2(SLC12A3):​c.1315G>A​(p.Gly439Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000799 in 1,613,822 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G439V) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000080 (0 hom.)
• Consequence: SLC12A3 NM_001126108.2 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:17
• Conservation: PhyloP100: 7.98

Genes affected

SLC12A3 (HGNC:10912): (solute carrier family 12 member 3) This gene encodes a renal thiazide-sensitive sodium-chloride cotransporter that is important for electrolyte homeostasis. This cotransporter mediates sodium and chloride reabsorption in the distal convoluted tubule. Mutations in this gene cause Gitelman syndrome, a disease similar to Bartter's syndrome, that is characterized by hypokalemic alkalosis combined with hypomagnesemia, low urinary calcium, and increased renin activity associated with normal blood pressure. This cotransporter is the target for thiazide diuretics that are used for treating high blood pressure. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-56879208-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3236716.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.875
• PP5: Variant 16-56879207-G-A is Pathogenic according to our data. Variant chr16-56879207-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 586601.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-56879207-G-A is described in Lovd as [Pathogenic]. Variant chr16-56879207-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC12A3	NM_001126108.2	c.1315G>A	p.Gly439Ser	missense_variant	10/26	ENST00000563236.6
SLC12A3	NM_000339.3	c.1315G>A	p.Gly439Ser	missense_variant	10/26
SLC12A3	NM_001126107.2	c.1312G>A	p.Gly438Ser	missense_variant	10/26
SLC12A3	NM_001410896.1	c.1312G>A	p.Gly438Ser	missense_variant	10/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC12A3	ENST00000563236.6	c.1315G>A	p.Gly439Ser	missense_variant	10/26	1	NM_001126108.2	A1
SLC12A3	ENST00000438926.6	c.1315G>A	p.Gly439Ser	missense_variant	10/26	1		A1
SLC12A3	ENST00000566786.5	c.1312G>A	p.Gly438Ser	missense_variant	10/26	1		P4
SLC12A3	ENST00000262502.5	c.1312G>A	p.Gly438Ser	missense_variant	10/26	5		A1

Frequencies

GnomAD3 genomes AF: 0.0000788 AC: 12 AN: 152206 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000163 AC: 41 AN: 250818 Hom.: 0 AF XY: 0.000133 AC XY: 18 AN XY: 135742

Gnomad AFR exome AF: 0.0000620

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000327

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000800 AC: 117 AN: 1461616 Hom.: 0 Cov.: 33 AF XY: 0.0000908 AC XY: 66 AN XY: 727110

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000752

Gnomad4 NFE exome AF: 0.0000971

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000788 AC: 12 AN: 152206 Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6 AN XY: 74362

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000285 Hom.: 1

Bravo AF: 0.000117

ExAC AF: 0.000231 AC: 28

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000296

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:17

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial hypokalemia-hypomagnesemia Pathogenic:9

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 10, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 11, 2019	Across a selection of the available literature, the SLC12A3 c.1315G>A (p.Gly439Ser) missense variant was found in a total of 15 individuals affected with Gitelman syndrome (GS). The p.Gly439Ser variant was found in a homozygous state in two individuals (one of whom was also homozygous for a second variant), in a compound heterozygous state in 12 individuals (including two siblings), and in a heterozygous state in one individual in whom a second variant was not identified (Mastroianni et al. 1996; Melander et al. 2000; Urbanová et al. 2006; Tajima et al 2006; Favre et al. 2012; Berry et al. 2013; Brambilla et al. 2013; Bouchireb et al. 2014). The variant was found in a heterozygous state in one of 844 control chromosomes and is reported at a frequency of 0.0004 in the non-Finnish European population of the Exome Aggregation Consortium. De Jong et al. (2002) demonstrated that Xenopus oocytes expressing the p.Gly439Ser variant showed no significant sodium uptake and exhibited significant cellular mislocalization of the protein. Based on the collective evidence, the p.Gly439Ser variant is classified as pathogenic for Gitelman syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, criteria provided, single submitter	clinical testing	European Hospital Georges Pompidou Genetics Department, Assistance Publique - Hôpitaux de Paris AP-HP	Apr 27, 2022	ACMG criteria used:PM1 PM2 PM3 PP3 PP5 -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota	May 23, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 29, 2022	- -
Pathogenic, criteria provided, single submitter	research	Molecular Biology Laboratory, Fundació Puigvert	Feb 01, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 13, 2024	Variant summary: SLC12A3 c.1315G>A (p.Gly439Ser) results in a non-conservative amino acid change located in the Amino acid permease/ SLC12A domain (IPR004841) 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 0.00016 in 250818 control chromosomes (gnomAD). c.1315G>A has been reported in the literature in multiple individuals affected with Gitelman syndrome (examples: Mastrojanni_1996, Horak_2005, and Fava_2007). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 8900229, 17654016, 16343108). ClinVar contains an entry for this variant (Variation ID: 586601). Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 22, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 11, 2023	Published functional studies demonstrate a damaging effect due to an intracellular trafficking defect, with failure to reach the cell membrane (De Jong et al., 2002); 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: 17159356, 19451210, 19349556, 17654016, 24790334, 28700713, 28469853, 23475471, 12039972, 8900229, 25112827, 26830254, 23328711, 18391953, 15102966, 10988270, 31672324, 26121437, 22241817, 22009145, 31398183, 31589614, 33348466) -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 24, 2023	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 439 of the SLC12A3 protein (p.Gly439Ser). This variant is present in population databases (rs759377924, gnomAD 0.03%). This missense change has been observed in individual(s) with Gitelman syndrome (PMID: 8900229, 17654016, 23475471, 25112827). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 586601). 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%. Experimental studies have shown that this missense change affects SLC12A3 function (PMID: 12039972). For these reasons, this variant has been classified as Pathogenic. -

Familial aortopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Mar 13, 2024

Variant summary: MYLK c.1315G>A (p.Gly439Arg) results in a non-conservative amino acid change located in the Immunoglobulin subtype 2 domain (IPR003598) 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 2.8e-05 in 248090 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1315G>A in individuals affected with Aortopathy and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 21, 2022

The c.1315G>A (p.G439S) alteration is located in exon 10 (coding exon 10) of the SLC12A3 gene. This alteration results from a G to A substitution at nucleotide position 1315, causing the glycine (G) at amino acid position 439 to be replaced by a serine (S). Based on data from gnomAD, the A allele has an overall frequency of 0.02% (44/282204) total alleles studied. The highest observed frequency was 0.03% (38/128698) of European (non-Finnish) alleles. This alteration has been detected in the homozygous state and as compound heterozygous in trans with other pathogenic SLC12A3 variants in multiple, unrelated individuals diagnosed with Gitelman syndrome (Mastroianni, 1996; Melander 2000; Urbanova, 2006; Tajima, 2006; Fava, 2007; Ji, 2008; Favre, 2012; Berry, 2013; Brambilla, 2013; Bouchireb, 2014; Bech, 2016; Zeng, 2019; Roser, 2020). This amino acid position is highly conserved in available vertebrate species. In vitro studies have shown that p.G439S results in the loss of function of the SLC12A3 protein (De Jong, 2002). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Bartter syndrome;C0268450:Familial hypokalemia-hypomagnesemia Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Sydney Genome Diagnostics, Children's Hospital Westmead

Aug 27, 2019

This individual is heterozygous for the c.1315G>A variant in the SLC12A3 gene, which results in the amino acid substitution of glycine to serine at residue 439, p.(Gly439Ser). This variant has been reported in the gnomAD browser (http://gnomad.broadinstitute.org) with a very low allele frequency of 0.015% (42 out of 276,658 alleles).This variant has been previously described in multiple individuals with Gitelman syndrome, in either a homozygous or compound heterozygous state (Bouchireb et al 2014 BMC Pediatrics 14: 201; Vargas-Poussou et al 2011 J Am Soc Nephrol 22: 693-703). In addition, functional studies, using Xenopus oocytes harbouring the p.(Gly439Ser) variant, showed a loss of sodium ion uptake and exhibited significant cellular mis-localisation of the protein (De Jong et al 2002 J Am Soc Nephrol 13: 1442-1448). This variant is considered to be pathogenic according to the ACMG guidelines. (Evidence used: PS3, PM2, PM3_strong). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	29
DANN	Uncertain	1.0
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.93	D;D;D;D
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.87	D;D;D;D
MetaSVM	Uncertain	0.0066	D
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-5.7	D;D;D;D
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D
Polyphen		1.0	D;D;D;.
Vest4		0.84
MVP		0.98
MPC		0.44
ClinPred		0.78	D
GERP RS		4.9
Varity_R		0.88
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs759377924; hg19: chr16-56913119;