rs199849117

Variant names:

• chr16-56913293-G-A
• rs199849117
• NM_001126108.2:c.2954G>A

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1 PP2 PP5_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 (★★). Synonymous variant affecting the same amino acid position (i.e. C985C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: SLC12A3 NM_001126108.2 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:11 U:1
• Conservation: PhyloP100: 8.00
• Publications: 19 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 11 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_001126108.2
• 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.
• PP5: Variant 16-56913293-G-A is Pathogenic according to our data. Variant chr16-56913293-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 448395.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC12A3	NM_001126108.2	c.2954G>A	p.Cys985Tyr	missense_variant	Exon 26 of 26	ENST00000563236.6	NP_001119580.2
SLC12A3	NM_000339.3	c.2981G>A	p.Cys994Tyr	missense_variant	Exon 26 of 26		NP_000330.3
SLC12A3	NM_001126107.2	c.2978G>A	p.Cys993Tyr	missense_variant	Exon 26 of 26		NP_001119579.2
SLC12A3	NM_001410896.1	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	c.2954G>A	p.Cys985Tyr	missense_variant	Exon 26 of 26	1	NM_001126108.2	ENSP00000456149.2

Frequencies

GnomAD3 genomes AF: 0.0000789 AC: 12 AN: 152162 Hom.: 0 Cov.: 32

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

GnomAD2 exomes AF: 0.000203 AC: 51 AN: 251292 AF XY: 0.000221

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 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.: 0 Cov.: 31 AF XY: 0.000147 AC XY: 107 AN XY: 727248

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

American (AMR) AF: 0.000425 AC: 19 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

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

European-Non Finnish (NFE) AF: 0.000177 AC: 197 AN: 1112010

Other (OTH) AF: 0.0000828 AC: 5 AN: 60396

GnomAD4 genome AF: 0.0000788 AC: 12 AN: 152280 Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5 AN XY: 74448

African (AFR) AF: 0.00 AC: 0 AN: 41566

American (AMR) AF: 0.00 AC: 0 AN: 15298

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000253 Hom.: 0

Bravo AF: 0.000117

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000247 AC: 30

EpiCase AF: 0.000491

EpiControl AF: 0.000296

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial hypokalemia-hypomagnesemia Pathogenic:7 Uncertain:1

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 30, 2021

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: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG criteria used:PS4 PS3 PM1 PM2 PM3 PP3 PP5 -

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. -

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 -

Aug 30, 2021

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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. -

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. -

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) -

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.85	.;.;D;D
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.73	T;T;T;T
M_CAP	Uncertain	0.18	D
MetaRNN	Uncertain	0.62	D;D;D;D
MetaSVM	Uncertain	0.025	D
MutationAssessor	Pathogenic	2.9	.;.;M;.
PhyloP100		8.0
PrimateAI	Uncertain	0.78	T
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	D
GERP RS		4.3
Varity_R		0.88
gMVP		0.70
Mutation Taster		=1/99	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: rs199849117; hg19: chr16-56947205;