ClinVar Genomic variation as it relates to human health
NM_001126108.2(SLC12A3):c.363G>C (p.Glu121Asp)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Likely pathogenic(3); Uncertain significance(6)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001126108.2(SLC12A3):c.363G>C (p.Glu121Asp)
Variation ID: 505768 Accession: VCV000505768.24
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 16q13 16: 56867150 (GRCh38) [ NCBI UCSC ] 16: 56901062 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Apr 9, 2018 May 1, 2024 Jan 29, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001126108.2:c.363G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001119580.2:p.Glu121Asp missense NM_000339.3:c.363G>C NP_000330.3:p.Glu121Asp missense NM_001126107.2:c.360G>C NP_001119579.2:p.Glu120Asp missense NC_000016.10:g.56867150G>C NC_000016.9:g.56901062G>C NG_009386.2:g.6944G>C - Protein change
- E121D, E120D
- Other names
- -
- Canonical SPDI
- NC_000016.10:56867149:G:C
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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0.00040 (C)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
1000 Genomes Project 0.00040
1000 Genomes Project 30x 0.00047
Exome Aggregation Consortium (ExAC) 0.00078
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00092
The Genome Aggregation Database (gnomAD), exomes 0.00093
The Genome Aggregation Database (gnomAD) 0.00102
Trans-Omics for Precision Medicine (TOPMed) 0.00122
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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SLC12A3 | - | - |
GRCh38 GRCh37 |
1623 | 1717 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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Aug 15, 2023 | RCV000607947.9 | |
Uncertain significance (4) |
criteria provided, multiple submitters, no conflicts
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Jan 29, 2024 | RCV000681735.7 | |
Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Jul 15, 2021 | RCV000778470.11 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jul 27, 2021 | RCV002529351.4 | |
SLC12A3-related disorder
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Uncertain significance (1) |
criteria provided, single submitter
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Apr 4, 2023 | RCV003424170.4 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Likely pathogenic
(Jan 09, 2019)
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criteria provided, single submitter
Method: clinical testing
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Familial hypokalemia-hypomagnesemia
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000914725.1
First in ClinVar: May 27, 2019 Last updated: May 27, 2019 |
Comment:
The SLC12A3 c.363G>C (p.Glu121Asp) variant has been reported in two studies and is found in a total of three probands with Gitelman syndrome in a … (more)
The SLC12A3 c.363G>C (p.Glu121Asp) variant has been reported in two studies and is found in a total of three probands with Gitelman syndrome in a compound heterozygous state (Glaudemans et al. 2012; Berry et al. 2013). Control data are unavailable for this variant, which is reported at a frequency of 0.00132 in the European (non-Finnish) population of the Exome Aggregation Consortium. Functional studies in Xenopus oocytes demonstrated proper localization but sodium uptake was significantly reduced compared to wild type (Glaudemans et al. 2012). Based on the evidence, the p.Glu121Asp variant is classified as likely pathogenic for Gitelman syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
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Likely pathogenic
(Jun 30, 2021)
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criteria provided, single submitter
Method: clinical testing
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Familial hypokalemia-hypomagnesemia
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV001752679.1
First in ClinVar: Jul 18, 2021 Last updated: Jul 18, 2021
Comment:
This variant has been detected in individual(s) who were sent for testing of Renasight - kidney gene panel.
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Likely pathogenic
(Jul 15, 2021)
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criteria provided, single submitter
Method: clinical testing
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Familial hypokalemia-hypomagnesemia
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV002055283.1
First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022 |
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Uncertain significance
(Sep 07, 2022)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002598612.1
First in ClinVar: Nov 05, 2022 Last updated: Nov 05, 2022 |
Comment:
Variant summary: SLC12A3 c.363G>C (p.Glu121Asp) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign … (more)
Variant summary: SLC12A3 c.363G>C (p.Glu121Asp) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00093 in 250226 control chromosomes in the gnomAD database, including 1 homozygote. This frequency does not allow conclusions about variant significance. c.363G>C has been reported in the literature in individuals with Gitelman syndrome, at-least one of whom reported normal levels of urinary calcium (examples: Glaudemans_2012, and Berry 2013) and chronic kidney disease/urinary stone disease (example: Groopman_2019, Cogal_2021). These reports do not provide unequivocal conclusions about association of the variant with Familial Hypokalemia-Hypomagnesemia (Gitelman syndrome). At least one publication reports experimental evidence evaluating an impact on protein function in the Xenopus laevis oocyte system (example: Glaudemans_ 2012). The most pronounced variant effect results in approximately 30% of normal thiazide-sensitive NaCl cotransporter (NCC) activity and normal localization to the plasma membrane. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=2) and likely pathogenic (n=4). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. (less)
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Uncertain significance
(Sep 19, 2022)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV003244111.1
First in ClinVar: Feb 07, 2023 Last updated: Feb 07, 2023 |
Comment:
This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 121 of the SLC12A3 … (more)
This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 121 of the SLC12A3 protein (p.Glu121Asp). This variant is present in population databases (rs146632606, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with Gitelman syndrome (PMID: 22009145, 23328711, 31672324). ClinVar contains an entry for this variant (Variation ID: 505768). 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 not expected to disrupt SLC12A3 protein function. Experimental studies have shown that this missense change affects SLC12A3 function (PMID: 22009145). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
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Uncertain significance
(Aug 15, 2023)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV004027099.1
First in ClinVar: Aug 19, 2023 Last updated: Aug 19, 2023 |
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Uncertain significance
(Apr 04, 2023)
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criteria provided, single submitter
Method: clinical testing
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SLC12A3-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004106573.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The SLC12A3 c.363G>C variant is predicted to result in the amino acid substitution p.Glu121Asp. This variant has been reported to be causative for autosomal recessive … (more)
The SLC12A3 c.363G>C variant is predicted to result in the amino acid substitution p.Glu121Asp. This variant has been reported to be causative for autosomal recessive Gitelman Syndrome (Glaudemans et al. 2012. PubMed ID: 22009145; Berry et al. 2013. PubMed ID: 23328711; Hureaux et al. 2019. PubMed ID: 31672324, supplementary data; Groopman et al. 2019. PubMed ID: 30586318, supplementary data). One individual with suspected urinary stone disease also harbored this variant in the heterozygous state along with a second established causative variant in SLC12A3 (Cogal et al. 2021. PubMed ID: 34805638). Functional studies indicate that this variant affects the thiazide-sensitive NaCl cotransporter (NCC) activities through reducing the sodium uptake (Glaudemans et al. 2012. PubMed ID: 22009145). This variant is reported in 0.16% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-56901062-G-C). This variant is interpreted as likely pathogenic. (less)
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Uncertain Significance
(Jan 29, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000713176.3
First in ClinVar: Apr 09, 2018 Last updated: Apr 20, 2024 |
Comment:
The p.Glu121Asp variant in SLC12A3 has been reported in the compound heterozygous state in 6 individuals with symptoms or a diagnosis of Gitelman syndrome or … (more)
The p.Glu121Asp variant in SLC12A3 has been reported in the compound heterozygous state in 6 individuals with symptoms or a diagnosis of Gitelman syndrome or urinary stone disease, at least 4 of whom carried a second disease-causing SLC12A3 variant (Glaudemans 2012 PMID: 22009145, Berry 2013 PMID: 23328711, Groopman 2019 PMID: 30586318, Hureaux PMID: 31672324, Cogal 2021 PMID: 34805638). In at least one of these individuals, the reported levels of urinary calcium were normal. This variant has also been identified in 0.16% (110/68042) of European chromosomes by the Genome Aggregation Database (gnomAD v.3.1.2, http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID 505768). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In vitro functional studies provide some evidence that the p.Glu121Asp variant may impact protein function (Glaudemans 2012 PMID: 22009145); however, these types of assays may not accurately represent biological function. In summary, while there is some suspicion for a pathogenic role, the clinical significance of the p.Glu121Asp variant is uncertain. ACMG/AMP Criteria applied: PM3_Strong, PS3_Supporting. (less)
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Uncertain significance
(Jul 27, 2021)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV003681065.2
First in ClinVar: Feb 07, 2023 Last updated: May 01, 2024 |
Comment:
The c.363G>C (p.E121D) alteration is located in exon 2 (coding exon 2) of the SLC12A3 gene. This alteration results from a G to C substitution … (more)
The c.363G>C (p.E121D) alteration is located in exon 2 (coding exon 2) of the SLC12A3 gene. This alteration results from a G to C substitution at nucleotide position 363, causing the glutamic acid (E) at amino acid position 121 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. (less)
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Likely pathogenic
(Sep 16, 2018)
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no assertion criteria provided
Method: research
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not provided
Affected status: yes
Allele origin:
germline
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Gharavi Laboratory, Columbia University
Accession: SCV000809190.1
First in ClinVar: Oct 01, 2018 Last updated: Oct 01, 2018 |
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Uncertain significance
(Sep 16, 2020)
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no assertion criteria provided
Method: clinical testing
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Gitelman syndrome
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV001458483.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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Benign
(-)
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no assertion criteria provided
Method: clinical testing
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not specified
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001951956.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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Likely benign
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001973517.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021 |
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Comprehensive Genetic Analysis Reveals Complexity of Monogenic Urinary Stone Disease. | Cogal AG | Kidney international reports | 2021 | PMID: 34805638 |
High-throughput sequencing contributes to the diagnosis of tubulopathies and familial hypercalcemia hypocalciuria in adults. | Hureaux M | Kidney international | 2019 | PMID: 31672324 |
Diagnostic Utility of Exome Sequencing for Kidney Disease. | Groopman EE | The New England journal of medicine | 2019 | PMID: 30586318 |
Unexpected clinical sequelae of Gitelman syndrome: hypertension in adulthood is common and females have higher potassium requirements. | Berry MR | Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association | 2013 | PMID: 23328711 |
Novel NCC mutants and functional analysis in a new cohort of patients with Gitelman syndrome. | Glaudemans B | European journal of human genetics : EJHG | 2012 | PMID: 22009145 |
Text-mined citations for rs146632606 ...
HelpRecord last updated May 19, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.