rs749098014

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_001126108.2(SLC12A3):c.1180+1G>T variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000217 in 1,610,004 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

SLC12A3
NM_001126108.2 splice_donor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:16

Conservation

PhyloP100: 9.97

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 18 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 16-56878162-G-T is Pathogenic according to our data. Variant chr16-56878162-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 437426.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-56878162-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
SLC12A3	NM_001126108.2 link	c.1180+1G>T	splice_donor_variant, intron_variant	Intron 9 of 25	ENST00000563236.6	NP_001119580.2	P55017-1
SLC12A3	NM_000339.3 link	c.1180+1G>T	splice_donor_variant, intron_variant	Intron 9 of 25		NP_000330.3	P55017-2
SLC12A3	NM_001126107.2 link	c.1177+1G>T	splice_donor_variant, intron_variant	Intron 9 of 25		NP_001119579.2	P55017-3
SLC12A3	NM_001410896.1 link	c.1177+1G>T	splice_donor_variant, intron_variant	Intron 9 of 25		NP_001397825.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
SLC12A3	ENST00000563236.6 link	c.1180+1G>T	splice_donor_variant, intron_variant	Intron 9 of 25	1	NM_001126108.2	ENSP00000456149.2	P55017-1
SLC12A3	ENST00000438926.6 link	c.1180+1G>T	splice_donor_variant, intron_variant	Intron 9 of 25	1		ENSP00000402152.2	P55017-2
SLC12A3	ENST00000566786.5 link	c.1177+1G>T	splice_donor_variant, intron_variant	Intron 9 of 25	1		ENSP00000457552.1	P55017-3
SLC12A3	ENST00000262502.5 link	c.1177+1G>T	splice_donor_variant, intron_variant	Intron 9 of 25	5		ENSP00000262502.5	J3QSS1

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151796

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:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000282

AC:

AN:

248628

Hom.:

AF XY:

0.0000445

AC XY:

AN XY:

134784

show subpopulations

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 SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000442

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.0000226

AC:

AN:

1458208

Hom.:

Cov.:

AF XY:

0.0000221

AC XY:

AN XY:

725578

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000195

Gnomad4 NFE exome

AF:

0.0000252

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000132

AC:

AN:

151796

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74120

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:16

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial hypokalemia-hypomagnesemia

Pathogenic:13

May 02, 2023

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

The homozygous c.1180+1G>T variant in SLC12A3 was identified by our study in one individual with arthrogryposis multiplex congenita. The c.1180+1G>T variant in SLC12A3 has been reported in 50 unrelated individuals with Gitelman syndrome (PMID: 33532864, PMID: 33532864, PMID: 22009145, PMID: 21415153, SCV001427187.2, SCV000598146.1, PMID: 14675033, PMID: 16221718), segregated with disease in 20 affected relatives from 12 families (PMID: 14675033), but has been identified in 0.004% (5/112998) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs749098014). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. Of these 50 affected individuals, 37 were homozygotes (PMID: 33532864, PMID: 22009145, PMID: 21415153, SCV001427187.2, SCV000598146.1, PMID: 14675033, PMID: 16221718), two were compound heterozygotes who carried pathogenic or likely pathogenic variants in trans (PMID: 28325561; PMID: 21415153, ClinVar Variation ID: 1073480), and seven were presumed compound heterozygotes who carried pathogenic or likely pathogenic variants in unknown phase (PMID: 25422309, ClinVar Variation ID: 372504, ClinVar Variation ID: 586604; PMID: 21415153, ClinVar Variation ID: 1071754, ClinVar Variation ID: 974506, ClinVar Variation ID: 8584, ClinVar Variation ID: 437926, ClinVar Variation ID: 8591), which increases the likelihood that the c.1180+1G>T variant in SLC12A3 is pathogenic. This variant has also been reported in ClinVar (Variation ID: 437426) and has been interpreted as pathogenic by multiple submitters. RT-PCR analysis performed on affected tissue shows evidence of exon skipping of exon 9 (PMID: 16221718). This variant is located in the 3' splice region. Computational tools predict a splicing impact, though this information is not predictive enough to determine pathogenicity. Loss of function of the SLC12A3 gene is an established disease mechanism in Gitelman syndrome. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Gitelman syndrome. ACMG/AMP Criteria applied: PVS1, PS3_Moderate, PM2_Supporting, PM3_VeryStrong, PP1_Strong (Richards 2015) -

Mar 11, 2021

Molecular Genetics, Royal Melbourne Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects the canonical donor splice site in intron 9 of SLC12A3. It is a confirmed spliceogenic variant that causes exon 9 skipping in RNA splicing assays, which is expected to result in nonsense-mediate decay (PS3; PMID: 16221718). Loss of function is a well established mechanism of disease for SLC12A3 (PVS1). The variant is present in a large population cohort at a frequency of 0.003% (rs749098014, 7/248,628 alleles, 0 homozygotes in gnomAD v2.1.1 - PM2), which is consistent with a recessive disorder. It has been identified in the homozygous state or compound heterozygous with another pathogenic allele in at least 15 cases with a clinical diagnosis of Gitelman syndrome (PMID: 14675033, 25422309, 28325561 - PM3_VeryStrong). Based on the classification scheme RMH ACMG Guidelines v1.1.1, this variant is classified as PATHOGENIC. Following criteria are met: PVS1, PM3_VeryStrong, PS3, PM2. -

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 14, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 31, 2020

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

Jun 30, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 15, 2021

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 16, 2017

Center of Genomic medicine, Geneva, University Hospital of Geneva

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This homozygous variant in SLC12A3 gene was found in a young female patient with Gitelman syndrome -

Sep 02, 2022

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_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Gitelman syndrome (MIM#263800). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0211 - Canonical splice site variant without proven consequence on splicing (no functional evidence available). (SP) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (7 heterozygotes, 0 homozygotes). (SP) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is highly conserved. (SP) 0704 - Another canonical splice variant comparable to the one identified in this case has limited previous evidence for pathogenicity. The c.1180+2T>C variant has been classified as pathogenic by one clinical diagnostic laboratory (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by multiple clinical diagnostic laboratories and has been reported in both homozygous and compound heterozygous individuals with Gitelman syndrome (ClinVar, VCGS, PMIDs: 28325561, 14675033). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Mar 26, 2020

Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 05, 2021

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1, PS3, PM2, PP3, PP5 -

Feb 01, 2020

Molecular Biology Laboratory, Fundació Puigvert

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

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, PM1, PM2, PM3, PP3, PP5 -

not provided

Pathogenic:3

Nov 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects a donor splice site in intron 9 of the SLC12A3 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in SLC12A3 are known to be pathogenic (PMID: 20848653, 22009145, 25841442). This variant is present in population databases (rs749098014, gnomAD 0.005%). Disruption of this splice site has been observed in individuals with Gitelman syndrome (PMID: 14675033, 25422309, 28325561). This variant is also known as "intron 9 +1 G>T". ClinVar contains an entry for this variant (Variation ID: 437426). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Jan 23, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 22009145, 20412406, 25841442, 20848653, 26221292, 25422309, 28325561, 21753071, 32742169, 34426522, 31589614, 32939031, 31672324, 30586318, 16221718, 14675033) -

Sep 16, 2018

Gharavi Laboratory, Columbia University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.53

BayesDel_noAF

Pathogenic

0.35

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

1.3

Eigen_PC

Pathogenic

1.1

FATHMM_MKL

Pathogenic

0.98

GERP RS

5.8

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.93

SpliceAI score (max)

1.0

Details are displayed if max score is > 0.2

DS_DL_spliceai

1.0

Position offset: -1

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