NM_001126108.2:c.815T>C

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1PM2PP2PP3_StrongPP5_Very_Strong

The NM_001126108.2(SLC12A3):​c.815T>C​(p.Leu272Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000198 in 1,613,554 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

SLC12A3
NM_001126108.2 missense

Scores

14
4
1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 7.96

Publications

5 publications found
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 Gene-Disease associations (from GenCC):
  • Gitelman syndrome
    Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 17 ACMG points.

PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_001126108.2
PM2
Very rare variant in population databases, with high coverage;
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.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.974
PP5
Variant 16-56870699-T-C is Pathogenic according to our data. Variant chr16-56870699-T-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 209191.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-56870699-T-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 209191.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-56870699-T-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 209191.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-56870699-T-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 209191.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-56870699-T-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 209191.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-56870699-T-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 209191.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-56870699-T-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 209191.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-56870699-T-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 209191.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-56870699-T-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 209191.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-56870699-T-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 209191.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-56870699-T-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 209191.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-56870699-T-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 209191.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-56870699-T-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 209191.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-56870699-T-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 209191.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-56870699-T-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 209191.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-56870699-T-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 209191.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-56870699-T-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 209191.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-56870699-T-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 209191.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-56870699-T-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 209191.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-56870699-T-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 209191.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-56870699-T-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 209191.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-56870699-T-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 209191.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-56870699-T-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 209191.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-56870699-T-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 209191.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-56870699-T-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 209191.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-56870699-T-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 209191.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-56870699-T-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 209191.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-56870699-T-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 209191.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-56870699-T-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 209191.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
SLC12A3NM_001126108.2 linkc.815T>C p.Leu272Pro missense_variant Exon 6 of 26 ENST00000563236.6 NP_001119580.2 P55017-1
SLC12A3NM_000339.3 linkc.815T>C p.Leu272Pro missense_variant Exon 6 of 26 NP_000330.3 P55017-2
SLC12A3NM_001126107.2 linkc.812T>C p.Leu271Pro missense_variant Exon 6 of 26 NP_001119579.2 P55017-3
SLC12A3NM_001410896.1 linkc.812T>C p.Leu271Pro missense_variant Exon 6 of 26 NP_001397825.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SLC12A3ENST00000563236.6 linkc.815T>C p.Leu272Pro missense_variant Exon 6 of 26 1 NM_001126108.2 ENSP00000456149.2 P55017-1
SLC12A3ENST00000438926.6 linkc.815T>C p.Leu272Pro missense_variant Exon 6 of 26 1 ENSP00000402152.2 P55017-2
SLC12A3ENST00000566786.5 linkc.812T>C p.Leu271Pro missense_variant Exon 6 of 26 1 ENSP00000457552.1 P55017-3
SLC12A3ENST00000262502.5 linkc.812T>C p.Leu271Pro missense_variant Exon 6 of 26 5 ENSP00000262502.5 J3QSS1

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152182
Hom.:
0
Cov.:
32
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:
0.0000588
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000159
AC:
4
AN:
251392
AF XY:
0.0000147
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 FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000352
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000192
AC:
28
AN:
1461372
Hom.:
0
Cov.:
33
AF XY:
0.0000220
AC XY:
16
AN XY:
727018
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33470
American (AMR)
AF:
0.00
AC:
0
AN:
44722
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26134
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39698
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86250
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53418
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.0000243
AC:
27
AN:
1111540
Other (OTH)
AF:
0.0000166
AC:
1
AN:
60372
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.489
Heterozygous variant carriers
0
2
3
5
6
8
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152182
Hom.:
0
Cov.:
32
AF XY:
0.0000538
AC XY:
4
AN XY:
74352
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41460
American (AMR)
AF:
0.00
AC:
0
AN:
15280
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5196
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4832
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10616
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000588
AC:
4
AN:
68008
Other (OTH)
AF:
0.00
AC:
0
AN:
2092
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.488
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.0000293
Hom.:
0
Bravo
AF:
0.00000756

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:4
Dec 14, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 272 of the SLC12A3 protein (p.Leu272Pro). This variant is present in population databases (rs568513106, gnomAD 0.004%). This missense change has been observed in individuals with Gitelman syndrome (PMID: 18391953, 31398183). ClinVar contains an entry for this variant (Variation ID: 209191). 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%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

-
Genome Diagnostics Laboratory, University Medical Center Utrecht
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Sep 16, 2018
Gharavi Laboratory, Columbia University
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:research

- -

-
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Familial hypokalemia-hypomagnesemia Pathogenic:3
-
Baylor Genetics
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Jun 24, 2024
Fulgent Genetics, Fulgent Genetics
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Dec 04, 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.815T>C (p.Leu272Pro) results in a non-conservative amino acid change located in the Amino acid permease/ SLC12A domain (IPR004841) 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 1.6e-05 in 251392 control chromosomes (gnomAD). c.815T>C has been reported in the literature in multiple compound heterozygous individuals affected with Gitelman syndrome (Ji_2008, Glaudemans_2011, Peng_2017, Zhang_2023). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 22009145, 18391953, 28700713, 21415153, 36806220). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.98
BayesDel_addAF
Pathogenic
0.49
D
BayesDel_noAF
Pathogenic
0.57
CADD
Pathogenic
28
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.97
.;.;D;D
Eigen
Pathogenic
0.88
Eigen_PC
Pathogenic
0.80
FATHMM_MKL
Uncertain
0.90
D
LIST_S2
Uncertain
0.95
D;D;D;D
M_CAP
Pathogenic
0.55
D
MetaRNN
Pathogenic
0.97
D;D;D;D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Pathogenic
3.9
.;H;H;.
PhyloP100
8.0
PrimateAI
Uncertain
0.79
T
PROVEAN
Pathogenic
-6.5
D;D;D;D
REVEL
Pathogenic
0.98
Sift
Pathogenic
0.0
D;D;D;D
Sift4G
Uncertain
0.0020
D;D;D;D
Polyphen
1.0
D;D;D;.
Vest4
0.98
MVP
0.98
MPC
0.60
ClinPred
1.0
D
GERP RS
5.0
Varity_R
0.98
gMVP
0.99
Mutation Taster
=0/100
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

Publications

Other links and lift over

dbSNP: rs568513106; hg19: chr16-56904611; API