16-56884142-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong

The NM_001126108.2(SLC12A3):c.1763C>T(p.Ala588Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000248 in 1,614,074 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A588E) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

SLC12A3
NM_001126108.2 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 7.81

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 transmembrane_region Helical (size 20) in uniprot entity S12A3_HUMAN there are 5 pathogenic changes around while only 1 benign (83%) 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 chr16-56884142-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2137825.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.917

PP5

Variant 16-56884142-C-T is Pathogenic according to our data. Variant chr16-56884142-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 8591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-56884142-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
SLC12A3	NM_001126108.2 linkuse as main transcript	c.1763C>T	p.Ala588Val	missense_variant	14/26	ENST00000563236.6
SLC12A3	NM_000339.3 linkuse as main transcript	c.1763C>T	p.Ala588Val	missense_variant	14/26
SLC12A3	NM_001126107.2 linkuse as main transcript	c.1760C>T	p.Ala587Val	missense_variant	14/26
SLC12A3	NM_001410896.1 linkuse as main transcript	c.1760C>T	p.Ala587Val	missense_variant	14/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC12A3	ENST00000563236.6 linkuse as main transcript	c.1763C>T	p.Ala588Val	missense_variant	14/26	1	NM_001126108.2	A1	P55017-1
SLC12A3	ENST00000438926.6 linkuse as main transcript	c.1763C>T	p.Ala588Val	missense_variant	14/26	1		A1	P55017-2
SLC12A3	ENST00000566786.5 linkuse as main transcript	c.1760C>T	p.Ala587Val	missense_variant	14/26	1		P4	P55017-3
SLC12A3	ENST00000262502.5 linkuse as main transcript	c.1760C>T	p.Ala587Val	missense_variant	14/26	5		A1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

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:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000239

AC:

AN:

251084

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135738

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000882

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000246

AC:

AN:

1461846

Hom.:

Cov.:

AF XY:

0.0000316

AC XY:

AN XY:

727226

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000176

Gnomad4 SAS exome

AF:

0.000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000135

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152228

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74364

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ExAC

AF:

0.0000412

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial hypokalemia-hypomagnesemia

Pathogenic:3

Likely pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 1996	- -
Pathogenic, criteria provided, single submitter	clinical testing	DASA	Jan 05, 2022	The c.1763C>T;p.(Ala588Val) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 8591; OMIM: 600968.0008; PMID: 17329572; 23328711) - PS4. Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID: 17329572) - PS3_supporting. The variant is present at low allele frequencies population databases (rs121909382– gnomAD 0.0002628%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Ala588Val) was detected in trans with a pathogenic variant (PMID: 23328711) - PM3. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic. -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 08, 2024	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 588 of the SLC12A3 protein (p.Ala588Val). This variant is present in population databases (rs121909382, gnomAD 0.02%). This missense change has been observed in individuals with Gitelman syndrome (PMID: 17329572, 23328711). ClinVar contains an entry for this variant (Variation ID: 8591). 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: 17329572). This variant disrupts the p.Ala588 amino acid residue in SLC12A3. Other variant(s) that disrupt this residue have been observed in individuals with SLC12A3-related conditions (PMID: 23328711), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 16, 2022	Published functional studies demonstrate the same level of activity as non-injected oocytes, a positive intracellular and plasma membrane staining, and complex glycosylation and presence in both cell surface and cytoplasm contrasting with a lack of intrinsic activity (Riveira-Munoz et al., 2007); 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: 30305584, 27872838, 17329572, 8528245, 31589614, 33348466, 33775700, 23328711) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.61

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.52

Cadd

Pathogenic

Dann

Pathogenic

1.0

Eigen

Pathogenic

0.75

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.98

D;D;D;D

M_CAP

Pathogenic

0.60

MetaRNN

Pathogenic

0.92

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationTaster

Benign

1.0

A;A;A;A

PrimateAI

Uncertain

0.59

PROVEAN

Uncertain

-3.6

D;D;D;D

Sift

Uncertain

0.0020

D;D;D;D

Sift4G

Uncertain

0.0080

D;D;D;D

Polyphen

0.97

D;D;D;.

Vest4

0.79

MVP

0.99

MPC

0.45

ClinPred

0.82

GERP RS

5.0

Varity_R

0.68

gMVP

0.92

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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