ClinVar Genomic variation as it relates to human health
NM_001126108.2(SLC12A3):c.1924C>G (p.Arg642Gly)
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001126108.2(SLC12A3):c.1924C>G (p.Arg642Gly)
Variation ID: 397523 Accession: VCV000397523.18
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 16q13 16: 56885363 (GRCh38) [ NCBI UCSC ] 16: 56919275 (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 Mar 27, 2017 Feb 20, 2024 Dec 19, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001126108.2:c.1924C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001119580.2:p.Arg642Gly missense NM_000339.2:c.[1924C>G] NM_000339.3:c.1924C>G NP_000330.3:p.Arg642Gly missense NM_001126107.2:c.1921C>G NP_001119579.2:p.Arg641Gly missense NC_000016.10:g.56885363C>G NC_000016.9:g.56919275C>G NG_009386.1:g.25157C>G - Protein change
- R642G, R641G
- Other names
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- Canonical SPDI
- NC_000016.10:56885362:C:G
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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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0.00020 (T)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00025
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 |
1626 | 1720 |
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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Pathogenic/Likely pathogenic (6) |
criteria provided, multiple submitters, no conflicts
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Apr 27, 2022 | RCV000449562.12 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Dec 19, 2023 | RCV001239291.10 |
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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Pathogenic
(Dec 15, 2014)
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criteria provided, single submitter
Method: clinical testing
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Familial hypokalemia-hypomagnesemia
Affected status: yes
Allele origin:
germline
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Center of Genomic medicine, Geneva, University Hospital of Geneva
Accession: SCV000537713.1
First in ClinVar: Mar 27, 2017 Last updated: Mar 27, 2017 |
Age: 15-20 years
Sex: male
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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: SCV002055338.1
First in ClinVar: Jan 12, 2022 Last updated: Jan 12, 2022 |
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Likely pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Familial hypokalemia-hypomagnesemia
Affected status: yes
Allele origin:
germline
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Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV002073059.1
First in ClinVar: Feb 04, 2022 Last updated: Feb 04, 2022 |
Comment:
The missense variant p.R642G in SLC12A3 (NM_000339.3) has been previously reported in affected patients (Syren ML et al; Corbetta S et al). The variant was … (more)
The missense variant p.R642G in SLC12A3 (NM_000339.3) has been previously reported in affected patients (Syren ML et al; Corbetta S et al). The variant was submitted to ClinVar as Pathogenic. The p.R642G variant is observed in 4/62,126 (0.0064%) alleles from individuals of European (Non-Finnish) background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The p.R642G missense variant is predicted to be damaging by both SIFT and PolyPhen2. The arginine residue at codon 642 of SLC12A3 is conserved in all mammalian species. The nucleotide c.1924 in SLC12A3 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. In the absence of functional studies this variant has been classified as Likely Pathogenic. (less)
Clinical Features:
Decreased serum testosterone concentration (present) , Elevated circulating follicle stimulating hormone level (present)
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Pathogenic
(Apr 27, 2022)
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criteria provided, single submitter
Method: clinical testing
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Familial hypokalemia-hypomagnesemia
Affected status: yes
Allele origin:
germline
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European Hospital Georges Pompidou Genetics Department, Assistance Publique - Hôpitaux de Paris AP-HP
Accession: SCV002513810.1
First in ClinVar: May 21, 2022 Last updated: May 21, 2022
Comment:
ACMG criteria used:PS4, PM1, PM2, PM3, PM5, PP3, PP5
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Comment:
ACMG criteria used:PS4, PM1, PM2, PM3, PM5, PP3, PP5
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Pathogenic
(Dec 22, 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: SCV002779538.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Sep 27, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV002072818.3
First in ClinVar: Feb 04, 2022 Last updated: Oct 05, 2023 |
Comment:
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: 12112667, … (more)
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: 12112667, 31028937, 22009145, 11168953, 20675610, 25422309, 11408395, 32397528, 33542107, 34604727, 34768847, 35894287, 36302598, 34532947, 34373523, 35785516) (less)
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Pathogenic
(Dec 19, 2023)
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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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001412151.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 642 of the SLC12A3 protein (p.Arg642Gly). … (more)
This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 642 of the SLC12A3 protein (p.Arg642Gly). This variant is present in population databases (rs200697179, gnomAD 0.007%). This missense change has been observed in individual(s) with Gitelman syndrome (PMID: 11408395, 12112667, 25422309). 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. ClinVar contains an entry for this variant (Variation ID: 397523). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Mar 03, 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: SCV002089359.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
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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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Urinary exosomes in the diagnosis of Gitelman and Bartter syndromes. | Corbetta S | Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association | 2015 | PMID: 25422309 |
Identification of fifteen novel mutations in the SLC12A3 gene encoding the Na-Cl Co-transporter in Italian patients with Gitelman syndrome. | Syrén ML | Human mutation | 2002 | PMID: 12112667 |
Mutations in the Na-Cl cotransporter reduce blood pressure in humans. | Cruz DN | Hypertension (Dallas, Tex. : 1979) | 2001 | PMID: 11408395 |
Text-mined citations for rs200697179 ...
HelpRecord last updated Sep 29, 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.