rs34803727

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong

The NM_001126108.2(SLC12A3):c.2938G>A(p.Gly980Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000148 in 1,614,068 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00016 ( 0 hom. )

Consequence

SLC12A3
NM_001126108.2 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14

Conservation

PhyloP100: 4.79

Variant links:

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]

SLC12A3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 16-56913277-G-A is Pathogenic according to our data. Variant chr16-56913277-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 586605.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-56913277-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC12A3	NM_001126108.2 link	c.2938G>A	p.Gly980Arg	missense_variant	Exon 26 of 26	ENST00000563236.6	NP_001119580.2	P55017-1
SLC12A3	NM_000339.3 link	c.2965G>A	p.Gly989Arg	missense_variant	Exon 26 of 26		NP_000330.3	P55017-2
SLC12A3	NM_001126107.2 link	c.2962G>A	p.Gly988Arg	missense_variant	Exon 26 of 26		NP_001119579.2	P55017-3
SLC12A3	NM_001410896.1 link	c.2935G>A	p.Gly979Arg	missense_variant	Exon 26 of 26		NP_001397825.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC12A3	ENST00000563236.6 link	c.2938G>A	p.Gly980Arg	missense_variant	Exon 26 of 26	1	NM_001126108.2	ENSP00000456149.2		P55017-1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000558

AC:

AN:

251000

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

135754

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000106

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000159

AC:

232

AN:

1461888

Hom.:

Cov.:

AF XY:

0.000149

AC XY:

108

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000203

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152180

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74340

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000119

Hom.:

Bravo

AF:

0.0000340

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000659

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial hypokalemia-hypomagnesemia

Pathogenic:6

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 11, 2022

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 27, 2022

European Hospital Georges Pompidou Genetics Department, Assistance Publique - Hôpitaux de Paris AP-HP

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG criteria used:PS3, PS4, PM1, PM2, PM3, PP1, PP5 -

Oct 10, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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 glycine to arginine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 17 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated SLC12 family domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as likely pathogenic and pathogenic by multiple clinical diagnostic laboratories and is associated with Gitelman syndrome (ClinVar, PMID: 11168953). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Jul 15, 2021

Genome-Nilou Lab

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:6

Jan 06, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In vitro functional analysis demonstrated significantly diminished metolazone-sensitive sodium uptake levels in cells harboring this variant; immunocytochemical analysis revealed that the altered protein was localized to the cytoplasm and plasma membrane rather than only the plasma membrane as observed with the wild-type protein (De Jong et al., 2002); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Also known as p.(G980R); This variant is associated with the following publications: (PMID: 23328711, 21415153, 11168953, 22009145, 31672324, 33144682, 17329572, 29942493, 18391953, 12039972) -

Apr 10, 2018

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SLC12A3: PM3:Very Strong, PM2, PS3:Supporting -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 989 of the SLC12A3 protein (p.Gly989Arg). This variant is present in population databases (rs34803727, gnomAD 0.01%). This missense change has been observed in individual(s) with Gitelman syndrome (PMID: 17329572, 18391953, 21415153, 23328711, 29942493). 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 c.2938G>A (G980R). ClinVar contains an entry for this variant (Variation ID: 586605). Invitae Evidence 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 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. Experimental studies have shown that this missense change affects SLC12A3 function (PMID: 12039972). For these reasons, this variant has been classified as Pathogenic. -

Inborn genetic diseases

Pathogenic:1

Nov 12, 2020

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2965G>A (p.G989R) alteration is located in exon 26 (coding exon 26) of the SLC12A3 gene. This alteration results from a G to A substitution at nucleotide position 2965, causing the glycine (G) at amino acid position 989 to be replaced by an arginine (R). Based on data from the Genome Aggregation Database (gnomAD) database, the SLC12A3 c.2965G>A alteration was observed in 0.006% (17/282,386) of total alleles studied, with a frequency of 0.01% (14/128,704) in the European (non-Finnish) subpopulation. This alteration has been reported in multiple patients with Gitelman syndrome in both the homozygous and compound heterozygous states (Berry, 2013; Glaudemans, 2012; Vargas-Poussou, 2011; Ji, 2008). This amino acid position is not well conserved in available vertebrate species. In an assay of metolazone-sensitive sodium uptake this variant was found to be functionally abnormal (de Jong, 2002). The in silico prediction for the p.G989R alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic. -

Bartter syndrome;C0268450:Familial hypokalemia-hypomagnesemia

Pathogenic:1

Jul 13, 2018

Sydney Genome Diagnostics, Children's Hospital Westmead

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This individual is heterozygous for the c.2965G>A variant in the SLC12A3 gene. This variant has been reported in the gnomAD browser (http://gnomad.broadinstitute.org) with a very low allele frequency of 0.006% (16 out of 276,718 alleles). The c.2965G>A p.(Gly989Arg) variant, which is equivalent to c.2938G>A p.(Gly980Arg) using transcript NM_001126108.1, has been described in many patients with Gitelman syndrome as compound heterozygous with a second pathogenic variant (e.g. De Jong et al. 2002 J Am Soc Nephrol 13: 1442-1448; Riveira-Munoz et al. 2007 J Am Soc Nephrol 18: 1271-1283; Ji et al. 2008 Nat Genet 40: 592-599). Functional studies found that the mutant protein had impaired sodium ion uptake and was also partially incorrectly localised in the cytoplasm (De Jong et al. 2002 J Am Soc Nephrol 13: 1442-1448). This variant is considered to be pathogenic according to the ACMG guidelines. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.75

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Pathogenic

0.24

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.47

.;.;T;T

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Uncertain

0.83

LIST_S2

Uncertain

0.94

D;D;D;D

M_CAP

Uncertain

0.11

MetaRNN

Uncertain

0.47

T;T;T;T

MetaSVM

Uncertain

-0.23

MutationAssessor

Uncertain

2.5

.;.;M;.

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-1.9

N;N;N;N

REVEL

Benign

0.27

Sift

Uncertain

0.014

D;D;D;D

Sift4G

Uncertain

0.026

D;D;D;D

Polyphen

0.94

P;D;D;.

Vest4

0.67

MutPred

0.81

.;.;Gain of MoRF binding (P = 0.0334);.;

MVP

0.92

MPC

0.46

ClinPred

0.32

GERP RS

4.3

Varity_R

0.63

gMVP

0.84

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over