rs121909379

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong

The NM_001126108.2(SLC12A3):c.2549T>C(p.Leu850Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000155 in 1,613,836 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. L850F) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

SLC12A3
NM_001126108.2 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12

Conservation

PhyloP100: 7.74

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.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr16-56894557-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1490589.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.979

PP5

Variant 16-56894558-T-C is Pathogenic according to our data. Variant chr16-56894558-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 8584.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-56894558-T-C 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.2549T>C	p.Leu850Pro	missense_variant	22/26	ENST00000563236.6
SLC12A3	NM_000339.3 linkuse as main transcript	c.2576T>C	p.Leu859Pro	missense_variant	22/26
SLC12A3	NM_001126107.2 linkuse as main transcript	c.2573T>C	p.Leu858Pro	missense_variant	22/26
SLC12A3	NM_001410896.1 linkuse as main transcript	c.2546T>C	p.Leu849Pro	missense_variant	22/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC12A3	ENST00000563236.6 linkuse as main transcript	c.2549T>C	p.Leu850Pro	missense_variant	22/26	1	NM_001126108.2	A1	P55017-1
SLC12A3	ENST00000438926.6 linkuse as main transcript	c.2576T>C	p.Leu859Pro	missense_variant	22/26	1		A1	P55017-2
SLC12A3	ENST00000566786.5 linkuse as main transcript	c.2573T>C	p.Leu858Pro	missense_variant	22/26	1		P4	P55017-3
SLC12A3	ENST00000262502.5 linkuse as main transcript	c.2546T>C	p.Leu849Pro	missense_variant	22/26	5		A1

Frequencies

GnomAD3 genomes

AF:

0.000164

AC:

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000916

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:

0.000132

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.000115

AC:

AN:

251130

Hom.:

AF XY:

0.000111

AC XY:

AN XY:

135712

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000434

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS 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:

0.000154

AC:

225

AN:

1461690

Hom.:

Cov.:

AF XY:

0.000168

AC XY:

122

AN XY:

727108

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000403

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000181

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.000164

AC:

AN:

152146

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74322

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000916

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.000479

Alfa

AF:

0.0000880

Hom.:

Bravo

AF:

0.000113

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.0000988

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial hypokalemia-hypomagnesemia

Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	European Hospital Georges Pompidou Genetics Department, Assistance Publique - Hôpitaux de Paris AP-HP	Apr 27, 2022	ACMG criteria used:PS3, PS4, PM2, PM3, PP3, PP5 -
Pathogenic, no assertion criteria provided	clinical testing	Baylor Genetics	Jan 29, 2022	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 1996	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 22, 2021	- -

not provided

Pathogenic:4

Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2024	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 859 of the SLC12A3 protein (p.Leu859Pro). This variant is present in population databases (rs121909379, gnomAD 0.04%). This missense change has been observed in individual(s) with SLC12A3-related conditions (PMID: 8528245, 19016647, 21415153, 23328711, 27582097). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as p.Leu850Pro. ClinVar contains an entry for this variant (Variation ID: 8584). 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: 27582097). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 27, 2023	Published functional studies demonstrate a damaging effect due to decreased expression and significantly lower activity of the sodium-chloride cotransporter (NCC) compared to wild-type, impaired NCC glycosylation, and disrupted NCC phosphorylation (Valdez-Flores et al., 2016); 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, 19016647, 27582097, 31672324, 23328711, 21753071, 31589614, 36314956, 34604727, 35591852, 21415153) -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 14, 2022

The c.2576T>C (p.L859P) alteration is located in exon 22 (coding exon 22) of the SLC12A3 gene. This alteration results from a T to C substitution at nucleotide position 2576, causing the leucine (L) at amino acid position 859 to be replaced by a proline (P). Based on data from gnomAD, the C allele has an overall frequency of 0.012% (33/282520) total alleles studied. The highest observed frequency was 0.042% (15/35392) of Latino alleles. This variant has been reported in the homozygous state in multiple individuals with Gitelman syndrome and in conjunction with a second variant in SLC12A3 in individuals with Gitelman syndrome (Simon, 1996; Ji, 2008; Vargas-Poussou, 2011; Berry, 2013; Hureaux, 2019). This amino acid position is well conserved in available vertebrate species. Functional assays demonstrate reduced enzyme activity, protein abundance, post-translation modifications and aberrant protein localization in vitro (Valdez-Flores, 2016). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

SLC12A3-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 21, 2022

The SLC12A3 c.2576T>C variant is predicted to result in the amino acid substitution p.Leu859Pro. This variant has been reported in the homozygous and compound heterozygous states in several individuals with Gitelman syndrome (reported as L850P in Simon et al. 1996. PubMed ID: 8528245; Supplemental tables in Vargas-Poussou et al. 2011. PubMed ID: 21415153; Berry et al. 2013. PubMed ID: 23328711). Functional studies in HEK293 cells indicated this variant results in significantly decreased NaCl cotransporter activity (Valdez-Flores et al. 2016. PubMed ID: 27582097). This variant is reported in 0.042% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-56928470-T-C). This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Pathogenic

0.43

Cadd

Pathogenic

Dann

Uncertain

1.0

Eigen

Pathogenic

0.74

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.91

D;D;D;D

M_CAP

Pathogenic

0.53

MetaRNN

Pathogenic

0.98

D;D;D;D

MetaSVM

Pathogenic

0.97

MutationTaster

Benign

1.0

A;A;A;A

PrimateAI

Uncertain

0.72

PROVEAN

Pathogenic

-6.2

D;D;D;D

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Pathogenic

0.0010

D;D;D;D

Polyphen

1.0

D;D;D;.

Vest4

0.98

MVP

0.98

MPC

0.60

ClinPred

0.92

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.97

gMVP

0.96

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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