rs146632606

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM1BP4_ModerateBS2

The NM_001126108.2(SLC12A3):c.363G>C(p.Glu121Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00152 in 1,614,098 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0010 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0016 ( 2 hom. )

Consequence

SLC12A3
NM_001126108.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:7B:2

Conservation

PhyloP100: 0.782

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 Likely_benign. Variant got -4 ACMG points.

PM1

In a topological_domain Cytoplasmic (size 134) in uniprot entity S12A3_HUMAN there are 5 pathogenic changes around while only 2 benign (71%) in NM_001126108.2

BP4

Computational evidence support a benign effect (MetaRNN=0.07202932).

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC12A3	NM_001126108.2 link	c.363G>C	p.Glu121Asp	missense_variant	Exon 2 of 26	ENST00000563236.6	NP_001119580.2	P55017-1
SLC12A3	NM_000339.3 link	c.363G>C	p.Glu121Asp	missense_variant	Exon 2 of 26		NP_000330.3	P55017-2
SLC12A3	NM_001126107.2 link	c.360G>C	p.Glu120Asp	missense_variant	Exon 2 of 26		NP_001119579.2	P55017-3
SLC12A3	NM_001410896.1 link	c.360G>C	p.Glu120Asp	missense_variant	Exon 2 of 26		NP_001397825.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SLC12A3	ENST00000563236.6 link	c.363G>C	p.Glu121Asp	missense_variant	Exon 2 of 26	1	NM_001126108.2	ENSP00000456149.2	P55017-1
SLC12A3	ENST00000438926.6 link	c.363G>C	p.Glu121Asp	missense_variant	Exon 2 of 26	1		ENSP00000402152.2	P55017-2
SLC12A3	ENST00000566786.5 link	c.360G>C	p.Glu120Asp	missense_variant	Exon 2 of 26	1		ENSP00000457552.1	P55017-3
SLC12A3	ENST00000262502.5 link	c.360G>C	p.Glu120Asp	missense_variant	Exon 2 of 26	5		ENSP00000262502.5	J3QSS1

Frequencies

GnomAD3 genomes

AF:

0.000999

AC:

152

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000362

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00150

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00162

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000927

AC:

232

AN:

250226

Hom.:

AF XY:

0.000982

AC XY:

133

AN XY:

135466

show subpopulations

Gnomad AFR exome

AF:

0.000248

Gnomad AMR exome

AF:

0.000898

Gnomad ASJ exome

AF:

0.000399

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000464

Gnomad NFE exome

AF:

0.00167

Gnomad OTH exome

AF:

0.000491

GnomAD4 exome

AF:

0.00157

AC:

2302

AN:

1461770

Hom.:

Cov.:

AF XY:

0.00148

AC XY:

1074

AN XY:

727172

show subpopulations

Gnomad4 AFR exome

AF:

0.000269

Gnomad4 AMR exome

AF:

0.000895

Gnomad4 ASJ exome

AF:

0.000498

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000696

Gnomad4 FIN exome

AF:

0.0000375

Gnomad4 NFE exome

AF:

0.00195

Gnomad4 OTH exome

AF:

0.00104

GnomAD4 genome

AF:

0.000998

AC:

152

AN:

152328

Hom.:

Cov.:

AF XY:

0.000859

AC XY:

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.000361

Gnomad4 AMR

AF:

0.00150

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00162

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.00169

Hom.:

Bravo

AF:

0.00122

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00208

AC:

ESP6500AA

AF:

0.000455

AC:

ESP6500EA

AF:

0.00116

AC:

ExAC

AF:

0.000758

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00147

EpiControl

AF:

0.00148

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:7Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Familial hypokalemia-hypomagnesemia

Pathogenic:3Uncertain:1

Jul 15, 2021

Genome-Nilou Lab

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 30, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 09, 2019

Illumina Laboratory Services, Illumina

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The SLC12A3 c.363G>C (p.Glu121Asp) variant has been reported in two studies and is found in a total of three probands with Gitelman syndrome in a compound heterozygous state (Glaudemans et al. 2012; Berry et al. 2013). Control data are unavailable for this variant, which is reported at a frequency of 0.00132 in the European (non-Finnish) population of the Exome Aggregation Consortium. Functional studies in Xenopus oocytes demonstrated proper localization but sodium uptake was significantly reduced compared to wild type (Glaudemans et al. 2012). Based on the evidence, the p.Glu121Asp 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. -

not provided

Pathogenic:1Uncertain:2Benign:1

Sep 16, 2018

Gharavi Laboratory, Columbia University

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

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

Significance: Likely benign

Review Status: flagged submission

Collection Method: clinical testing

- -

Jan 15, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 121 of the SLC12A3 protein (p.Glu121Asp). This variant is present in population databases (rs146632606, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with Gitelman syndrome (PMID: 22009145, 23328711, 30586318, 31672324). ClinVar contains an entry for this variant (Variation ID: 505768). 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 not expected to disrupt SLC12A3 protein function with a negative predictive value of 95%. Experimental studies have shown that this missense change affects SLC12A3 function (PMID: 22009145). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Jan 29, 2024

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Glu121Asp variant in SLC12A3 has been reported in the compound heterozygous state in 6 individuals with symptoms or a diagnosis of Gitelman syndrome or urinary stone disease, at least 4 of whom carried a second disease-causing SLC12A3 variant (Glaudemans 2012 PMID: 22009145, Berry 2013 PMID: 23328711, Groopman 2019 PMID: 30586318, Hureaux PMID: 31672324, Cogal 2021 PMID: 34805638). In at least one of these individuals, the reported levels of urinary calcium were normal. This variant has also been identified in 0.16% (110/68042) of European chromosomes by the Genome Aggregation Database (gnomAD v.3.1.2, http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID 505768). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In vitro functional studies provide some evidence that the p.Glu121Asp variant may impact protein function (Glaudemans 2012 PMID: 22009145); however, these types of assays may not accurately represent biological function. In summary, while there is some suspicion for a pathogenic role, the clinical significance of the p.Glu121Asp variant is uncertain. ACMG/AMP Criteria applied: PM3_Strong, PS3_Supporting. -

not specified

Uncertain:2Benign:1

Jan 06, 2025

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: SLC12A3 c.363G>C (p.Glu121Asp) results in a conservative amino acid change in the encoded protein sequence. Three of three in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00093 in 250226 control chromosomes in the gnomAD database, including 1 homozygote. 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.363G>C has been reported in the literature in individuals with Gitelman syndrome, at-least one of whom reported normal levels of urinary calcium (examples: Glaudemans_2012, and Berry 2013) and chronic kidney disease/urinary stone disease (example: Groopman_2019, Cogal_2021). These reports do not provide unequivocal conclusions about association of the variant with Familial Hypokalemia-Hypomagnesemia (Gitelman syndrome). At least one publication reports experimental evidence evaluating an impact on protein function in the Xenopus laevis oocyte system (example: Glaudemans_ 2012). The most pronounced variant effect results in approximately 30% of normal thiazide-sensitive NaCl cotransporter (NCC) activity and normal localization to the plasma membrane. The following publications have been ascertained in the context of this evaluation (PMID: 23328711, 34805638, 22009145, 30586318). ClinVar contains an entry for this variant (Variation ID: 505768). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

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

Significance: Benign

Review Status: flagged submission

Collection Method: clinical testing

- -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases

Uncertain:1

Jul 27, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.363G>C (p.E121D) alteration is located in exon 2 (coding exon 2) of the SLC12A3 gene. This alteration results from a G to C substitution at nucleotide position 363, causing the glutamic acid (E) at amino acid position 121 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

SLC12A3-related disorder

Uncertain:1

Jun 21, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The SLC12A3 c.363G>C variant is predicted to result in the amino acid substitution p.Glu121Asp. This variant has been reported with a second SLC12A3 variant in at least 6 individuals with presumed Gitelman Syndrome (Glaudemans et al. 2012. PubMed ID: 22009145; Berry et al. 2013. PubMed ID: 23328711; Hureaux et al. 2019. PubMed ID: 31672324, supplementary data; Groopman et al. 2019. PubMed ID: 30586318, supplementary data). One individual with suspected urinary stone disease also harbored this variant in the heterozygous state along with a SLC34A1 variant (PHN133, Cogal et al. 2021. PubMed ID: 34805638). Functional studies indicate that this variant affects the thiazide-sensitive NaCl cotransporter (NCC) activities through reducing the sodium uptake (Glaudemans et al. 2012. PubMed ID: 22009145). This amino acid position is moderately conserved and Asp is located at this position in Tetraodon (Alamut Visual Plus v1.6.1). This variant is reported in 0.16% of alleles in individuals of European (non-Finnish) descent in gnomAD V2. In the more recent gnomAD V4 data, this variant is observed in 2454/1,614,098 (0.15%) alleles and in 2 homozygotes, which may be too common to be a primary cause of disease (https://gnomad.broadinstitute.org/variant/16-56867150-G-C?dataset=gnomad_r4). Although we suspect this variant could possibly contribute to SLC12A3-related disorders, given the conflicting evidence, the clinical significance of this variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Uncertain

-0.050

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.15

.;.;T;T

Eigen

Benign

-0.14

Eigen_PC

Benign

0.037

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.76

T;T;T;T

M_CAP

Benign

0.014

MetaRNN

Benign

0.072

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.1

.;L;L;.

PrimateAI

Benign

0.40

PROVEAN

Benign

-0.25

N;N;N;N

REVEL

Benign

0.22

Sift

Benign

0.19

T;T;T;T

Sift4G

Benign

0.36

T;T;T;T

Polyphen

0.0

B;B;B;.

Vest4

0.67

MutPred

0.17

.;Gain of catalytic residue at G123 (P = 0.1393);Gain of catalytic residue at G123 (P = 0.1393);.;

MVP

0.86

MPC

0.081

ClinPred

0.013

GERP RS

4.7

Varity_R

0.10

gMVP

0.60

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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