NM_001126108.2:c.1964G>A

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PM1PM5PP2PP3_ModeratePP5_Very_Strong

The NM_001126108.2(SLC12A3):c.1964G>A(p.Arg655His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000124 in 1,613,892 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R655C) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000099 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00013 ( 0 hom. )

Consequence

SLC12A3
NM_001126108.2 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12U:1

Conservation

PhyloP100: 8.07

Publications

10 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 15 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_001126108.2

PM5

Other missense variant is known to change same aminoacid residue: Variant chr16-56886401-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 840885.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.855

PP5

Variant 16-56886402-G-A is Pathogenic according to our data. Variant chr16-56886402-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 8588.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
SLC12A3	NM_001126108.2 link	c.1964G>A	p.Arg655His	missense_variant	Exon 16 of 26	ENST00000563236.6	NP_001119580.2
SLC12A3	NM_000339.3 link	c.1964G>A	p.Arg655His	missense_variant	Exon 16 of 26		NP_000330.3
SLC12A3	NM_001126107.2 link	c.1961G>A	p.Arg654His	missense_variant	Exon 16 of 26		NP_001119579.2
SLC12A3	NM_001410896.1 link	c.1961G>A	p.Arg654His	missense_variant	Exon 16 of 26		NP_001397825.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
SLC12A3	ENST00000563236.6 link	c.1964G>A	p.Arg655His	missense_variant	Exon 16 of 26	1	NM_001126108.2	ENSP00000456149.2
SLC12A3	ENST00000438926.6 link	c.1964G>A	p.Arg655His	missense_variant	Exon 16 of 26	1		ENSP00000402152.2
SLC12A3	ENST00000566786.5 link	c.1961G>A	p.Arg654His	missense_variant	Exon 16 of 26	1		ENSP00000457552.1
SLC12A3	ENST00000262502.5 link	c.1961G>A	p.Arg654His	missense_variant	Exon 16 of 26	5		ENSP00000262502.5

Frequencies

GnomAD3 genomes

AF:

0.0000986

AC:

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

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:

0.000118

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.0000797

AC:

AN:

251024

AF XY:

0.000110

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.000199

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000123

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000127

AC:

185

AN:

1461742

Hom.:

Cov.:

AF XY:

0.000136

AC XY:

AN XY:

727182

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.0000447

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.000115

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53302

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000152

AC:

169

AN:

1111994

Other (OTH)

AF:

0.000132

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000986

AC:

AN:

152150

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74342

show subpopulations

African (AFR)

AF:

0.000145

AC:

AN:

41446

American (AMR)

AF:

0.00

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000118

AC:

AN:

68014

Other (OTH)

AF:

0.000478

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

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:

0.000251

Hom.:

Bravo

AF:

0.0000793

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000659

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial hypokalemia-hypomagnesemia

Pathogenic:9

Feb 01, 2020

Molecular Biology Laboratory, Fundació Puigvert

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Jan 01, 1996

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Mar 17, 2021

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 15, 2021

Genome-Nilou Lab

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 29, 2022

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.1964G>A (p.Arg655His) 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 8e-05 in 251024 control chromosomes. This frequency does not allow conclusions about variant significance. c.1964G>A has been reported in the literature in multiple individuals affected with Familial Hypokalemia-Hypomagnesemia, Gitelman syndrome (GS) (example, PMID: 33532864, 22009145, 19207868, 17329572, 32542819). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 (P/LP, n=7; VUS, n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -

Mar 02, 2024

Fulgent Genetics, Fulgent Genetics

Significance: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:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ACMG criteria used:PS4, PM1, PM2, PM5, PP3, PP5 -

Mar 29, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 23, 2023

3billion

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.008%). Predicted Consequence/Location: Missense variant In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.54 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.86 (>=0.6, sensitivity 0.72 and precision 0.9)]. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000008588 /PMID: 8528245). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PMID: 11168953, 22934535, 24776766). Different missense changes at the same codon (p.Arg655Cys, p.Arg655Leu) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000008589, VCV000840885 /PMID: 8528245, 9734597). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

not provided

Pathogenic:3

Feb 09, 2017

Athena Diagnostics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 655 of the SLC12A3 protein (p.Arg655His). This variant is present in population databases (rs121909380, gnomAD 0.02%). This missense change has been observed in individuals with Gitelman syndrome (PMID: 11168953, 22009145, 22934535, 24776766). ClinVar contains an entry for this variant (Variation ID: 8588). 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%. This variant disrupts the p.Arg655 amino acid residue in SLC12A3. Other variant(s) that disrupt this residue have been observed in individuals with SLC12A3-related conditions (PMID: 9734597, 11168953, 22214629), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Mar 16, 2025

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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, 11168953, 22934535, 26990548, 17329572, 12590198, 8900229, 28469853, 12112667, 34426522, 24776766, 22009145, 19207868, 31398183, 33996672, 31672324, 33226606, 33532864, Guven[CaseReport]2021, 35591852, 28700713, 35628451) -

Bartter syndrome;C0268450:Familial hypokalemia-hypomagnesemia

Uncertain:1

Feb 02, 2018

Sydney Genome Diagnostics, Children's Hospital Westmead

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

This individual is heterozygous for a known pathogenic variant, c.2883+1G>T, in the SLC12A3 gene. The c.2883+1G>T variant (dbSNP: rs199974259) has been reported in the gnomAD browser with a low allelic frequency of 0.02% (62 out of 276,340 alleles, http://gnomad.broadinstitute.org). This variant is predicted to abolish the consensus splice donor site at c.2883, resulting in the skipping of exon 24. This splice site variant has been previously reported in numerous patients with Gitelman syndrome in the literature (Vargas-Poussou et al 2011 J Am Soc Nephrol 22:693-703; Glaudemans et al 2012 Eur J Hum Genet 20:263-270). This variant is considered to be pathogenic according to the ACMG guidelines. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.40

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.41

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.83

.;.;D;T

Eigen

Pathogenic

0.72

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Uncertain

0.93

LIST_S2

Pathogenic

1.0

D;D;D;D

M_CAP

Uncertain

0.13

MetaRNN

Pathogenic

0.85

D;D;D;D

MetaSVM

Uncertain

0.26

MutationAssessor

Pathogenic

3.4

.;M;M;.

PhyloP100

8.1

PrimateAI

Uncertain

0.69

PROVEAN

Pathogenic

-4.8

D;D;D;D

REVEL

Uncertain

0.54

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

1.0

D;D;D;.

Vest4

0.96

MVP

0.97

MPC

0.53

ClinPred

0.95

GERP RS

3.1

Varity_R

0.90

gMVP

0.89

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

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

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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