16-56886402-G-A

Variant names:

• chr16-56886402-G-A
• rs121909380
• NM_001126108.2:c.1964G>A

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PM1 PM5 PP2 PP3_Moderate PP5_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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14 U:1
• Conservation: PhyloP100: 8.07
• Publications: 10 publications found

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)

ACMG classification

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001126108.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC12A3	NM_001126108.2	MANE Select	c.1964G>A	p.Arg655His	missense	Exon 16 of 26	NP_001119580.2
	SLC12A3	NM_000339.3		c.1964G>A	p.Arg655His	missense	Exon 16 of 26	NP_000330.3
	SLC12A3	NM_001126107.2		c.1961G>A	p.Arg654His	missense	Exon 16 of 26	NP_001119579.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC12A3	ENST00000563236.6	TSL:1 MANE Select	c.1964G>A	p.Arg655His	missense	Exon 16 of 26	ENSP00000456149.2
	SLC12A3	ENST00000438926.6	TSL:1	c.1964G>A	p.Arg655His	missense	Exon 16 of 26	ENSP00000402152.2
	SLC12A3	ENST00000566786.5	TSL:1	c.1961G>A	p.Arg654His	missense	Exon 16 of 26	ENSP00000457552.1

Frequencies

GnomAD3 genomes AF: 0.0000986 AC: 15 AN: 152150 Hom.: 0 Cov.: 32

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: 20 AN: 251024 AF XY: 0.000110

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.: 0 Cov.: 32 AF XY: 0.000136 AC XY: 99 AN XY: 727182

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000447 AC: 2 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53302

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000152 AC: 169 AN: 1111994

Other (OTH) AF: 0.000132 AC: 8 AN: 60392

GnomAD4 genome AF: 0.0000986 AC: 15 AN: 152150 Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5 AN XY: 74342

African (AFR) AF: 0.000145 AC: 6 AN: 41446

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68014

Other (OTH) AF: 0.000478 AC: 1 AN: 2090

Alfa AF: 0.000251 Hom.: 0

Bravo AF: 0.0000793

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000659 AC: 8

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial hypokalemia-hypomagnesemia Pathogenic:11

Mar 02, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 27, 2025

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Pathogenic. Evidence in support of pathogenic classification: Variant is present in gnomAD <0.01 for a recessive condition (v4: 200 heterozygote(s), 0 homozygote(s)); This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant is classified as likely pathogenic/pathogenic by clinical laboratories in ClinVar, and reported in individuals with Gitelman syndrome in the literature (PMID: 33996672, 33226606, 35628451). Additional information: Variant is predicted to result in a missense amino acid change from arginine to histidine; This variant is homozygous; This gene is associated with autosomal recessive disease; Multiple alternative amino acid changes at the same position have been observed in gnomAD (highest allele count v4: 37 heterozygote(s), 0 homozygote(s)); Variant is located in the annotated SLC12 domain (DECIPHER); Missense variant with conflicting in silico predictions and uninformative conservation; Loss of function is a known mechanism of disease in this gene and is associated with Gitelman syndrome (MIM#263800); Inheritance information for this variant is not currently available in this individual.

Feb 01, 2020

Molecular Biology Laboratory, Fundació Puigvert

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

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

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

Jan 01, 1996

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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.

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.

Sep 09, 2025

Department of Molecular Genetics, Istishari Arab Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The SLC12A3 variant c.1964G>A p.(Arg655His) causes an amino acid change from Arg to His at position 655 in exon(s) no. 16 (of 26). According to HGMD Professional 2023.3, this variant has previously been described as disease causing for Gitelman syndrome (PMID: 8528245, 33532864, 31672324). In-house, this variant was previously reported as disease-causing in 2 patients with Gitelman syndrome. It is classified as pathogenic (class 1) according to the recommendations of ACMG/AMP/ClinGen SVI guidelines.

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

not provided Pathogenic:3

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.

Feb 09, 2017

Athena Diagnostics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.83	D
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Uncertain	0.26	D
MutationAssessor	Pathogenic	3.4	M
PhyloP100		8.1
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Uncertain	0.54
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.96
MVP		0.97
MPC		0.53
ClinPred		0.95	D
GERP RS		3.1
Varity_R		0.90
gMVP		0.89
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121909380; hg19: chr16-56920314;