chr16-56887967-G-A

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1PP2PP5_Very_Strong

The NM_001126108.2(SLC12A3):c.2221G>A(p.Gly741Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000764 in 1,612,942 control chromosomes in the GnomAD database, with no homozygous occurrence. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.00041 ( 0 hom., cov: 30)

Exomes 𝑓: 0.00080 ( 0 hom. )

Consequence

SLC12A3
NM_001126108.2 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:26

Conservation

PhyloP100: 9.83

Publications

30 publications found

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 Gene-Disease associations (from GenCC):

Gitelman syndrome
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

SLC12A3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 11 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_001126108.2

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 138 curated pathogenic missense variants (we use a threshold of 10). The gene has 18 curated benign missense variants. Gene score misZ: -0.93606 (below the threshold of 3.09). Trascript score misZ: 0.71313 (below the threshold of 3.09). GenCC associations: The gene is linked to Gitelman syndrome.

PP5

Variant 16-56887967-G-A is Pathogenic according to our data. Variant chr16-56887967-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 208612.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC12A3	NM_001126108.2 link	c.2221G>A	p.Gly741Arg	missense_variant	Exon 18 of 26	ENST00000563236.6	NP_001119580.2	P55017-1
SLC12A3	NM_000339.3 link	c.2221G>A	p.Gly741Arg	missense_variant	Exon 18 of 26		NP_000330.3	P55017-2
SLC12A3	NM_001126107.2 link	c.2218G>A	p.Gly740Arg	missense_variant	Exon 18 of 26		NP_001119579.2	P55017-3
SLC12A3	NM_001410896.1 link	c.2218G>A	p.Gly740Arg	missense_variant	Exon 18 of 26		NP_001397825.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SLC12A3	ENST00000563236.6 link	c.2221G>A	p.Gly741Arg	missense_variant	Exon 18 of 26	1	NM_001126108.2	ENSP00000456149.2	P55017-1
SLC12A3	ENST00000438926.6 link	c.2221G>A	p.Gly741Arg	missense_variant	Exon 18 of 26	1		ENSP00000402152.2	P55017-2
SLC12A3	ENST00000566786.5 link	c.2218G>A	p.Gly740Arg	missense_variant	Exon 18 of 26	1		ENSP00000457552.1	P55017-3
SLC12A3	ENST00000262502.5 link	c.2218G>A	p.Gly740Arg	missense_variant	Exon 18 of 26	5		ENSP00000262502.5	J3QSS1

Frequencies

GnomAD3 genomes

AF:

0.000408

AC:

AN:

151816

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.000794

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.000370

AC:

AN:

251298

AF XY:

0.000346

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000202

Gnomad ASJ exome

AF:

0.000199

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000695

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000802

AC:

1171

AN:

1461010

Hom.:

Cov.:

AF XY:

0.000788

AC XY:

573

AN XY:

726842

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

33458

American (AMR)

AF:

0.000313

AC:

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.000383

AC:

AN:

26112

East Asian (EAS)

AF:

0.00

AC:

AN:

39668

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53222

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00101

AC:

1120

AN:

1111488

Other (OTH)

AF:

0.000348

AC:

AN:

60340

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

108

161

215

269

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

138

184

230

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000408

AC:

AN:

151932

Hom.:

Cov.:

AF XY:

0.000390

AC XY:

AN XY:

74276

show subpopulations

African (AFR)

AF:

0.000121

AC:

AN:

41418

American (AMR)

AF:

0.000131

AC:

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5156

South Asian (SAS)

AF:

0.00

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10528

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000795

AC:

AN:

67966

Other (OTH)

AF:

0.000474

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.523

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000549

Hom.:

Bravo

AF:

0.000389

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.000404

AC:

EpiCase

AF:

0.000382

EpiControl

AF:

0.000889

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:26

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial hypokalemia-hypomagnesemia

Pathogenic:13

Feb 10, 2025

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: SLC12A3 c.2221G>A (p.Gly741Arg) results in a non-conservative amino acid change in 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 0.00037 in 251298 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in SLC12A3 causing Familial Hypokalemia-Hypomagnesemia, allowing no conclusion about variant significance. c.2221G>A has been reported in the literature in multiple individuals affected with Familial Hypokalemia-Hypomagnesemia (example: Ashton_2018). These data indicate that the variant is very likely to be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 29398133). ClinVar contains an entry for this variant (Variation ID: 208612). Based on the evidence outlined above, the variant was classified as pathogenic. -

Dec 06, 2018

CENTOGENE GmbH and LLC - Guiding Precision Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 26, 2021

MGZ Medical Genetics Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 17, 2023

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 (v2) <0.01 for a recessive condition (104 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools and highly conserved with a major amino acid change. (SP) 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 pathogenic by at least fifteen clinical diagnostic laboratories and has been reported as one of the five most frequent pathogenic missense variants associated with Gitelman syndrome in Caucasians (ClinVar; PMID: 35591852). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

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 PP3 PP5 -

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant has been previously reported as a compound heterozygous change in patients with Gitelman syndrome (PMID: 8528245, 17329572, 21415153, 22009145, 23328711, 32939031). Functional studies have shown that this change results in reduced sodium uptake (PMID: 12039972). The c.2221G>A (p.Gly741Arg) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.03685% (104/282254) and is absent in the homozygous state, thus it is presumed to be rare. The c.2221G>A (p.Gly741Arg) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.2221G>A (p.Gly741Arg) variant is classified as Pathogenic. -

Jun 30, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 20, 2022

Genetics and Molecular Pathology, SA Pathology

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The SLC12A3 c.2221G>A variant is classified as Pathogenic (PS3, PM3_strong2, PP3) The SLC12A3 c.2221G>A variant is a single nucleotide change in exon 18/26 of the SLC12A3 gene, which is predicted to change the amino acid glycine at position 741 in the protein to arginine. Functional studies show that the variant results in a non-functional protein (PMID:12039972)(PS3). This variant has been detected in trans with pathogenic variants for this recessive condition (PMID:17329572) (PM3_strong). Computational predictions support a deleterious effect on the gene or gene product (PP3). The variant has been reported in dbSNP (rs138977195), in population databases (gnomAD 62/151816, 0 homs, highest freq 0.079% non-Finnish European) and as disease causing in the HGMD database (CM961300). It has been reported as Conflicting interpretations of pathogenicity by other diagnostic laboratories (ClinVar Variation ID: 208612). The variant has been widely reported in the literature in patients with Gitelman syndrome and has been described as a hotspot mutation (PMID:8528245, 12039972, 17329572, 21415153, 22009145). -

Mar 24, 2022

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PS3, PM2, PM3_Strong, PP3 -

Jul 15, 2021

Genome-Nilou Lab

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 12, 2021

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Across a selection of the available literature, the SLC12A3 c.2221G>A (p.Gly741Arg) missense variant has been reported in four patients with Gitelman syndrome in a homozygous state and in 79 patients in a compound heterozygous state (Simon et al. 1996; Vargas-Poussou et al. 2011; Glaudemans et al. 2012; Berry et al. 2013; Dongilli et al. 2016). Control data are not available for this variant which is reported at a frequency of 0.00063 in the European (non-Finnish) population of the Exome Aggregation Consortium. Functional studies in Xenopus oocytes demonstrated that the p.Gly741Arg variant resulted in no sodium ion uptake activity, showed intracellular localization rather than plasma membrane localization compared to wild type, and was not glycosylated (De Jong et al. 2002). Based on the collective evidence, the p.Gly741Arg 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. -

Feb 05, 2022

DASA

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.2221G>A;p.(Gly741Arg) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 208612; PMID: 18391953; 17329572; 21415153; 22009145; 23328711; 8528245) - PS4. The variant is present at low allele frequencies population databases (rs138977195 – gnomAD 0.0004084%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. The variant co-segregated with disease in multiple affected family members (PMID: 8528245) - PP1. In summary, the currently available evidence indicates that the variant is likely pathogenic. -

not provided

Pathogenic:9

Jun 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 11, 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 741 of the SLC12A3 protein (p.Gly741Arg). This variant is present in population databases (rs138977195, gnomAD 0.07%). This missense change has been observed in individual(s) with Gitelman syndrome (PMID: 8528245, 17329572, 18391953, 21415153, 22009145, 23328711). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 208612). 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) 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. -

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 predominantly localized to the cytoplasm rather than the plasma membrane as observed with the wild-type protein (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: 8528245, 18391953, 10988270, 9734597, 30201548, 23328711, 17329572, 21415153, 22009145, 26921350, 30596175, 31916727, 31980526, 30136149, 32939031, 31672324, 12039972, 27535533) -

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

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 15, 2023

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 28, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PP3, PM3_very_strong, PS3_supporting, PS4 -

Sep 16, 2018

Gharavi Laboratory, Columbia University

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Jan 11, 2024

Athena Diagnostics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The frequency of this variant in the general population is consistent with pathogenicity. (http://gnomad.broadinstitute.org) Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 12039972) In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Bartter syndrome;C0268450:Familial hypokalemia-hypomagnesemia

Pathogenic:1

Apr 05, 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.2221G>A variant in the SLC12A3 gene. This variant has been widely reported in numerous patients with Gitelman syndrome in the literature (Vargas-Poussou et al 2011 J Am Soc Nephrol 22:693-703. This variant is considered to be pathogenic according to the ACMG guidelines. -

Inherited renal tubular disease

Pathogenic:1

Sep 07, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

proposed classification - variant undergoing re-assessment, contact laboratory -

SLC12A3-related disorder

Pathogenic:1

Feb 22, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The SLC12A3 c.2221G>A variant is predicted to result in the amino acid substitution p.Gly741Arg. This variant has been reported in many unrelated individuals to be pathogenic for Gitelman syndrome (Simon et al. 1996. PubMed ID: 8528245; De Jong et al. 2002. PubMed ID: 12039972; Supp. Table 1 in Fujimura et al. 2018. PubMed ID: 30596175; Supp. Table S1 in Hureaux et al. 2019. PubMed ID: 31672324; Zacchia et al. 2021. PubMed ID: 33964006). Functional studies indicate that the p.Gly741Arg change impacts protein function (De Jong et al. 2002. PubMed ID: 12039972). This variant is reported in 0.068% of alleles in individuals of European (non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

Hypokalemia;C0151786:Muscle weakness;C0231528:Myalgia;C1522135:Hypermagnesemia

Pathogenic:1

Jan 01, 2017

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.55

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.89

.;.;D;D

Eigen

Pathogenic

0.71

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

1.0

D;D;D;D

M_CAP

Pathogenic

0.31

MetaRNN

Uncertain

0.70

D;D;D;D

MetaSVM

Uncertain

0.33

MutationAssessor

Pathogenic

3.5

.;H;H;.

PhyloP100

9.8

PrimateAI

Pathogenic

0.80

PROVEAN

Pathogenic

-7.4

D;D;D;D

REVEL

Pathogenic

0.85

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

1.0

D;D;D;.

Vest4

0.99

MutPred

0.89

.;Gain of MoRF binding (P = 0.0166);Gain of MoRF binding (P = 0.0166);.;

MVP

0.96

MPC

0.52

ClinPred

0.37

GERP RS

3.7

Varity_R

0.94

gMVP

0.94

Mutation Taster

=1/99

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over