rs199849117

Variant names:

Variant summary

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

The NM_001126108.2(SLC12A3):c.2954G>A(p.Cys985Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000144 in 1,614,172 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

SLC12A3
NM_001126108.2 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:11U:1

Conservation

PhyloP100: 8.00

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 16-56913293-G-A is Pathogenic according to our data. Variant chr16-56913293-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 448395.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-56913293-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.2954G>A	p.Cys985Tyr	missense_variant	Exon 26 of 26	ENST00000563236.6	NP_001119580.2	P55017-1
SLC12A3	NM_000339.3 link	c.2981G>A	p.Cys994Tyr	missense_variant	Exon 26 of 26		NP_000330.3	P55017-2
SLC12A3	NM_001126107.2 link	c.2978G>A	p.Cys993Tyr	missense_variant	Exon 26 of 26		NP_001119579.2	P55017-3
SLC12A3	NM_001410896.1 link	c.2951G>A	p.Cys984Tyr	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.2954G>A	p.Cys985Tyr	missense_variant	Exon 26 of 26	1	NM_001126108.2	ENSP00000456149.2		P55017-1

Frequencies

GnomAD3 genomes

AF:

0.0000789

AC:

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000176

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000203

AC:

AN:

251292

Hom.:

AF XY:

0.000221

AC XY:

AN XY:

135856

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000376

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:

0.000273

Gnomad OTH exome

AF:

0.00114

GnomAD4 exome

AF:

0.000151

AC:

221

AN:

1461892

Hom.:

Cov.:

AF XY:

0.000147

AC XY:

107

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000425

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:

0.000177

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.0000788

AC:

AN:

152280

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000176

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000308

Hom.:

Bravo

AF:

0.000117

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000247

AC:

EpiCase

AF:

0.000491

EpiControl

AF:

0.000296

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial hypokalemia-hypomagnesemia

Pathogenic:7Uncertain:1

Aug 30, 2021

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 15, 2021

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 13, 2024

Molecular Genetics, Royal Melbourne Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change in SLC12A3 is predicted to replace cysteine with tyrosine at codon 985, p.(Cys985Tyr). The cysteine residue is highly conserved (100 vertebrates, Multiz Alignments), and is located in the SLC12A transporter C-terminal domain, which is not a mutational hotspot or critical functional domain. There is a large physicochemical difference between cysteine and tyrosine. The highest population minor allele frequency in the population database gnomAD v4.1 is 0.03% (19/60,022 alleles) in the Admixed American population, which is consistent with recessive disease. ClinVar contains an entries for this variant (Variation ID: 448395). This variant has been detected in at least 15 individuals with Gitelman syndrome. Of those individuals, two individuals were homozygous and 13 were compound heterozygous for the variant and a pathogenic or likely pathogenic variant in SLC12A3 and three of those were confirmed in trans by parental testing (PMID: 29398133, 22009145, 12112667, 17329572, 21415153). Experimental studies in Xenopus laevis oocytes showed reduced metolazone-sensitive (22)Na(+) uptake relative to the wild-type, indicating that this variant impacts protein function (PMID: 12039972). Computational evidence is uninformative for the missense substitution (REVEL = 0.58). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: PM3_VeryStrong, PM2_Supporting, PS3_Supporting. -

Jan 27, 2023

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.2981G>A (p.Cys994Tyr) 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 0.0002 in 251292 control chromosomes. This frequency does not allow conclusions about variant significance. c.2981G>A has been reported in the literature as a biallelic genotype in multiple individuals affected with Familial Hypokalemia-Hypomagnesemia (Gitelman Syndrome) (example, PMID: 22009145, 29398133). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (example, PMID: 12039972), demonstrating significantly reduced metolazone-sensitive (22)Na(+) uptake relative to the wild-type thereby impacting functional outcomes. Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 (Pathogenic, n=9). Based on the evidence outlined above, the variant was classified as pathogenic. -

Nov 11, 2021

Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

PS3_moderate, PS4_moderate -

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:PS4 PS3 PM1 PM2 PM3 PP3 PP5 -

Jun 30, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:4

Oct 09, 2020

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). This variant is statistically more frequent in affected individuals than in the general population and/or healthy controls. This variant is also referred to as Cys985Tyr in published literature. Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant is shown to impair SLC12A3 protein trafficking to the plasma membrane (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. -

Dec 13, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 994 of the SLC12A3 protein (p.Cys994Tyr). This variant is present in population databases (rs199849117, gnomAD 0.03%). This missense change has been observed in individual(s) with Gitelman syndrome (PMID: 12112667, 21415153, 22009145, 23328711, 25422309). 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 p.Cys985Tyr. ClinVar contains an entry for this variant (Variation ID: 448395). 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. -

Dec 01, 2020

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 21, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect in Xenopus oocytes (PMID: 12039972); 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: 12112667, 17654016, 21415153, 31589614, 34860177, 20675610, 22990302, 21753071, 27216017, 34389731, 35591852, 35753512, 22009145, 25422309, 30136149, 12039972, 23328711, 31672324, 35628451, 30476936, 29398133) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.65

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Pathogenic

0.37

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.85

.;.;D;D

Eigen

Uncertain

0.68

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.73

T;T;T;T

M_CAP

Uncertain

0.18

MetaRNN

Uncertain

0.62

D;D;D;D

MetaSVM

Uncertain

0.025

MutationAssessor

Pathogenic

2.9

.;.;M;.

PrimateAI

Uncertain

0.78

PROVEAN

Pathogenic

-4.8

D;D;D;D

REVEL

Uncertain

0.58

Sift

Uncertain

0.0030

D;D;D;D

Sift4G

Uncertain

0.0050

D;D;D;D

Polyphen

0.99

D;D;D;.

Vest4

0.87

MVP

0.97

MPC

0.62

ClinPred

0.52

GERP RS

4.3

Varity_R

0.88

gMVP

0.70

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