rs371443644

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong

The NM_001126108.2(SLC12A3):c.179C>T(p.Thr60Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000316 in 1,614,094 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 Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000031 ( 0 hom. )

Consequence

SLC12A3
NM_001126108.2 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:14

Conservation

PhyloP100: 7.86

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 16 ACMG points.

PM1

In a topological_domain Cytoplasmic (size 134) in uniprot entity S12A3_HUMAN there are 5 pathogenic changes around while only 2 benign (71%) in NM_001126108.2

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.972

PP5

Variant 16-56865414-C-T is Pathogenic according to our data. Variant chr16-56865414-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 101514.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-56865414-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC12A3	NM_001126108.2 link	c.179C>T	p.Thr60Met	missense_variant	Exon 1 of 26	ENST00000563236.6	NP_001119580.2	P55017-1
SLC12A3	NM_000339.3 link	c.179C>T	p.Thr60Met	missense_variant	Exon 1 of 26		NP_000330.3	P55017-2
SLC12A3	NM_001126107.2 link	c.179C>T	p.Thr60Met	missense_variant	Exon 1 of 26		NP_001119579.2	P55017-3
SLC12A3	NM_001410896.1 link	c.179C>T	p.Thr60Met	missense_variant	Exon 1 of 26		NP_001397825.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SLC12A3	ENST00000563236.6 link	c.179C>T	p.Thr60Met	missense_variant	Exon 1 of 26	1	NM_001126108.2	ENSP00000456149.2	P55017-1
SLC12A3	ENST00000438926.6 link	c.179C>T	p.Thr60Met	missense_variant	Exon 1 of 26	1		ENSP00000402152.2	P55017-2
SLC12A3	ENST00000566786.5 link	c.179C>T	p.Thr60Met	missense_variant	Exon 1 of 26	1		ENSP00000457552.1	P55017-3
SLC12A3	ENST00000262502.5 link	c.179C>T	p.Thr60Met	missense_variant	Exon 1 of 26	5		ENSP00000262502.5	J3QSS1

Frequencies

GnomAD3 genomes

AF:

0.0000328

AC:

AN:

152228

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:

0.000770

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

GnomAD3 exomes

AF:

0.0000557

AC:

AN:

251452

Hom.:

AF XY:

0.0000662

AC XY:

AN XY:

135912

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000598

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000315

AC:

AN:

1461866

Hom.:

Cov.:

AF XY:

0.0000316

AC XY:

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000428

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000243

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152228

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74376

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000770

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000956

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.0000741

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial hypokalemia-hypomagnesemia

Pathogenic:11

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 09, 2020

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as 5-Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0106 - This gene is known to be associated with autosomal recessive disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from a threonine to a methionine (exon 1). (N) 0251 - Variant is heterozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (18 heterozygotes, 0 homozygotes). (P) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools and is highly conserved with a moderate amino acid change. (P) 0600 - Variant is located in an annotated domain or motif (AA permease N-terminal domain; PDB, DECIPHER). (N) 0801 - Strong previous evidence of pathogenicity in multiple unrelated individuals with Gitelman syndrome. (PMID: 22934535) (P) 0902 - Moderate evidence of variant segregating with disease in a family with 3 affected individuals (PMID: 18287808). (P) 1101 - Very strong and specific phenotype match. (P) 1201 - Heterozygous variant detected in trans with a second pathogenic heterozygous variant in a recessive disease (observed in IGV). (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -

Oct 01, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jan 06, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 02, 2021

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 4 similarly affected unrelated individuals (PMID:27454426, 27453715, 27173320, 24776766, 19451210, PM3_VS). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0000636, PM2). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.899, 3Cnet: 0.995, PP3). Patient's phenotype is considered compatible with Gitelman syndrome (3billion dataset, PP4). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

Aug 25, 2023

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS3, PM2, PM3_Strong, PP3 -

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:PS3, PS4, PM2, PP3, PP5 -

Feb 01, 2024

Department of Pediatrics, Taizhou Central Hospital, Taizhou University Hospital

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The SLC12A3 c.179C>T (p.Thr60Met) missense variant is well described in the literature and noted to be one of the most common pathogenic variants associated with Gitelman syndrome in the Asian population (Shao et al. 2012). The p.Thr60Met variant is described in at least eight studies in which it is found in a total of 35 patients, including in ten individuals in a homozygous state, in 20 individuals in a compound heterozygous state, and in five in a heterozygous state (Maki et al. 2004; Shao et al. 2008; Qin et al. 2009; Miao et al. 2009; Jiang et al. 2014; Kim et al. 2016; Miao et al. 2016; Ma et al. 2016). The variant was detected in a heterozygous state in four out of 510 control individuals and is reported at a frequency of 0.00092 in the East Asian population of the Exome Aggregation Consortium. Functional studies in transgenic mice demonstrated that the p.Thr60Met variant resulted in reduced targeting to the apical membranes of distal convoluted tubule cells due to impaired phosphorylation of the Thr60 residue (Yang et al. 2013). Functional studies in Xenopus demonstrated that the variant showed the same pattern of complex glycosylation and similar cell surface expression as wild type but the intrinsic activity of the protein was abolished (Miao et al. 2009). Based on the collective evidence, the p.Thr60Met variant is classified as pathogenic for Gitelman syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting+PS3_Moderate+PM3_VeryStrong+PP4 -

Jul 15, 2021

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:3

Mar 21, 2014

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 27, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported multiple times in the homozygous or compound heterozygous state in unrelated patients with Gitelman syndrome (Maki et al., 2004; Lin et al., 2004; Lin et al., 2005; Shao et al., 2008a; Shao et al. 2008b; Qin et al., 2009; Miao et al., 2009; Jiang et al., 2014; Yang et al., 2013); Published functional studies demonstrate p.(T60M) results in nearly complete loss of intrinsic transporter activity (Miao et al., 2009); 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: 23833262, 25990047, 19207868, 27173320, 29093260, 30596175, 24776766, 27453715, 26825084, 27216017, 27454426, 18580052, 30413979, 31672324, 31398183, 33024574, 32884933, 33163079, 34348722, 27535533, 33735743, 22627394, 19451210, 15069170) -

Jul 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 60 of the SLC12A3 protein (p.Thr60Met). This variant is present in population databases (rs371443644, gnomAD 0.08%). This missense change has been observed in individual(s) with Gitelman syndrome (PMID: 19207868, 19451210, 24776766, 27453715). 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 c.185C>T (p.T60M). ClinVar contains an entry for this variant (Variation ID: 101514). 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%. Experimental studies have shown that this missense change affects SLC12A3 function (PMID: 19451210, 23833262). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.58

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Pathogenic

0.48

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.94

.;.;D;D

Eigen

Pathogenic

0.70

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Uncertain

0.94

LIST_S2

Pathogenic

0.97

D;D;D;D

M_CAP

Pathogenic

0.41

MetaRNN

Pathogenic

0.97

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.5

M;M;M;.

PrimateAI

Uncertain

0.68

PROVEAN

Pathogenic

-5.0

D;D;D;D

REVEL

Pathogenic

0.90

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Pathogenic

0.0010

D;D;D;D

Polyphen

1.0

D;D;D;.

Vest4

0.96

MutPred

0.90

Loss of phosphorylation at T60 (P = 0.0568);Loss of phosphorylation at T60 (P = 0.0568);Loss of phosphorylation at T60 (P = 0.0568);Loss of phosphorylation at T60 (P = 0.0568);

MVP

0.99

MPC

0.48

ClinPred

0.82

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.93

gMVP

0.83

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