ClinVar Genomic variation as it relates to human health
NM_001126108.2(SLC12A3):c.1963C>T (p.Arg655Cys)
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
-
NM_001126108.2(SLC12A3):c.1963C>T (p.Arg655Cys)
Variation ID: 840885 Accession: VCV000840885.15
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 16q13 16: 56886401 (GRCh38) [ NCBI UCSC ] 16: 56920313 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 15, 2020 Feb 14, 2024 Dec 20, 2023 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_001126108.2:c.1963C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001119580.2:p.Arg655Cys missense NM_000339.3:c.1963C>T NP_000330.3:p.Arg655Cys missense NM_001126107.2:c.1960C>T NP_001119579.2:p.Arg654Cys missense NC_000016.10:g.56886401C>T NC_000016.9:g.56920313C>T NG_009386.2:g.26195C>T - Protein change
- R655C, R654C
- Other names
- -
- Canonical SPDI
- NC_000016.10:56886400:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
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.
-
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00003
- Links
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 | ||
---|---|---|---|---|---|---|
HI score
Help
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. |
|||
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. |
---|---|---|---|---|
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Dec 20, 2023 | RCV001042994.8 | |
Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Jul 15, 2021 | RCV001281278.7 |
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. |
|
---|---|---|---|---|---|
Likely pathogenic
(Feb 01, 2020)
|
criteria provided, single submitter
Method: research
|
Familial hypokalemia-hypomagnesemia
Affected status: yes
Allele origin:
germline
|
Molecular Biology Laboratory, Fundació Puigvert
Study: KidneyPanel_2020
Accession: SCV001425256.1 First in ClinVar: Jan 13, 2021 Last updated: Jan 13, 2021 |
|
|
Likely pathogenic
(Jul 15, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Familial hypokalemia-hypomagnesemia
Affected status: no
Allele origin:
germline
|
Genome-Nilou Lab
Accession: SCV002055343.1
First in ClinVar: Jan 12, 2022 Last updated: Jan 12, 2022 |
|
|
Likely pathogenic
(Mar 23, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV002575220.2
First in ClinVar: Oct 01, 2022 Last updated: Mar 04, 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: 12686679, … (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: 12686679, 22934535, 11168953, 22214629, 9734597, 30596175, 24776766, 31398183, 25422309, 23328711, 22009145, 31672324, 33532864) (less)
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
GITELMAN SYNDROME
Affected status: yes
Allele origin:
germline
|
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego
Accession: SCV004046306.1
First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023 |
Comment:
This variant has been previously reported as a compound heterozygous and homozygous change in patients with Gitelman syndrome (PMID: 31398183, 9734597, 22214629, 25422309, 23328711, 30596175). … (more)
This variant has been previously reported as a compound heterozygous and homozygous change in patients with Gitelman syndrome (PMID: 31398183, 9734597, 22214629, 25422309, 23328711, 30596175). Different amino acid changes at the same residue (p.Arg655His, p.Arg655Leu) have been previously reported in individuals with Gitelman syndrome (PMID:22934535, 22009145, 11168953, 24776766, 31398183). The c.1963C>T (p.Arg655Cys) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.002789% (7/250982) and is absent in the homozygous state, thus it is presumed to be rare. The c.1963C>T (p.Arg655Cys) variant affects a moderately conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.1963C>T (p.Arg655Cys) variant is classified as Pathogenic. (less)
|
|
Pathogenic
(Dec 20, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001206704.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 655 of the SLC12A3 protein … (more)
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 655 of the SLC12A3 protein (p.Arg655Cys). This variant is present in population databases (rs747249619, gnomAD 0.004%). This missense change has been observed in individuals with Gitelman syndrome (PMID: 9734597, 22214629, 23328711, 25422309). ClinVar contains an entry for this variant (Variation ID: 840885). 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%. This variant disrupts the p.Arg655 amino acid residue in SLC12A3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11168953, 22009145, 22934535, 24776766). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
Pathogenic
(Oct 05, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Gitelman syndrome
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV002089362.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
|
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 |
---|---|---|---|---|
Clinical utility of genetic testing in early-onset kidney disease: seven genes are the main players. | Domingo-Gallego A | Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association | 2022 | PMID: 33532864 |
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 |
Clinical severity of Gitelman syndrome determined by serum magnesium. | Jiang L | American journal of nephrology | 2014 | PMID: 24776766 |
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 missense mutations of WNK1 in patients with hypokalemic salt-losing tubulopathies. | Zhang C | Clinical genetics | 2013 | PMID: 22934535 |
Eplerenone improved hypokalemia in a patient with Gitelman's syndrome. | Ito Y | Internal medicine (Tokyo, Japan) | 2012 | PMID: 22214629 |
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 |
Gitelman's syndrome revisited: an evaluation of symptoms and health-related quality of life. | Cruz DN | Kidney international | 2001 | PMID: 11168953 |
Novel mutations in the thiazide-sensitive NaCl cotransporter gene in patients with Gitelman syndrome with predominant localization to the C-terminal domain. | Lemmink HH | Kidney international | 1998 | PMID: 9734597 |
Text-mined citations for rs747249619 ...
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.