16-56879088-G-T

Variant names:

• chr16-56879088-G-T
• rs13306668
• NM_001126108.2:c.1196G>T

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_001126108.2(SLC12A3):​c.1196G>T​(p.Arg399Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000335 in 1,611,700 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. R399H) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000036 (0 hom.)
• Consequence: SLC12A3 NM_001126108.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 7.58
• Publications: 9 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 17 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 4 uncertain in NM_001126108.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-56879088-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1489260.
• 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, 0.937
• PP5: Variant 16-56879088-G-T is Pathogenic according to our data. Variant chr16-56879088-G-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 381528.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.1196G>T	p.Arg399Leu	missense	Exon 10 of 26	NP_001119580.2
	SLC12A3	NM_000339.3		c.1196G>T	p.Arg399Leu	missense	Exon 10 of 26	NP_000330.3
	SLC12A3	NM_001126107.2		c.1193G>T	p.Arg398Leu	missense	Exon 10 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.1196G>T	p.Arg399Leu	missense	Exon 10 of 26	ENSP00000456149.2
	SLC12A3	ENST00000438926.6	TSL:1	c.1196G>T	p.Arg399Leu	missense	Exon 10 of 26	ENSP00000402152.2
	SLC12A3	ENST00000566786.5	TSL:1	c.1193G>T	p.Arg398Leu	missense	Exon 10 of 26	ENSP00000457552.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152170 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000283 AC: 7 AN: 247576 AF XY: 0.0000224

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000268

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.0000356 AC: 52 AN: 1459530 Hom.: 0 Cov.: 33 AF XY: 0.0000303 AC XY: 22 AN XY: 725936

African (AFR) AF: 0.00 AC: 0 AN: 33454

American (AMR) AF: 0.00 AC: 0 AN: 44462

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26070

East Asian (EAS) AF: 0.00 AC: 0 AN: 39674

South Asian (SAS) AF: 0.0000816 AC: 7 AN: 85826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53248

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5208

European-Non Finnish (NFE) AF: 0.0000351 AC: 39 AN: 1111306

Other (OTH) AF: 0.0000995 AC: 6 AN: 60282

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152170 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74344

African (AFR) AF: 0.0000241 AC: 1 AN: 41424

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000159 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial hypokalemia-hypomagnesemia Pathogenic:3

Jun 23, 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: 54 heterozygote(s), 0 homozygote(s)); This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic/likely pathogenic by clinical laboratories in ClinVar, and reported in the literature in a heterozygous or compound heterozygous state in individuals with Gitelman syndrome (PMIDs: 18391953, 23328711); Other missense variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. The p.(Arg399Cys), p.(Arg399Gly), and p.(Arg399Pro) variants have been classified as pathogenic/likely pathogenic by clinical laboratories in ClinVar. Additional information: Variant is predicted to result in a missense amino acid change from arginine to leucine; This variant is heterozygous; This gene is associated with autosomal recessive disease; Variant is located in the annotated amino acid permease domain (DECIPHER); Missense variant with inconclusive in silico prediction 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.

Nov 24, 2020

Natera, Inc.

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Dec 27, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Pathogenic:2

Jan 24, 2023

GeneDx

Significance: Likely 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: 23328711, 18391953)

Mar 05, 2024

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 leucine, which is neutral and non-polar, at codon 399 of the SLC12A3 protein (p.Arg399Leu). This variant is present in population databases (rs13306668, gnomAD 0.01%). This missense change has been observed in individuals with Gitelman syndrome (PMID: 18391953, 23328711). ClinVar contains an entry for this variant (Variation ID: 381528). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SLC12A3 protein function with a positive predictive value of 95%. This variant disrupts the p.Arg399 amino acid residue in SLC12A3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11168953, 17414160, 18391953, 25165177, 26121437). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Uncertain	0.29	D
MutationAssessor	Pathogenic	3.7	H
PhyloP100		7.6
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-6.7	D
REVEL	Uncertain	0.64
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.99	D
Vest4		0.85
MutPred		0.75		Loss of catalytic residue at R399 (P = 0.0614)
MVP		0.97
MPC		0.48
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.91
gMVP		0.98
Mutation Taster		=21/79	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs13306668; hg19: chr16-56913000;