ClinVar Genomic variation as it relates to human health
NM_001126108.2(SLC12A3):c.1924C>T (p.Arg642Cys)
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>T (p.Arg642Cys)
Variation ID: 944812 Accession: VCV000944812.10
- 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 Jul 16, 2020 Feb 14, 2024 Jan 29, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001126108.2:c.1924C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001119580.2:p.Arg642Cys missense NM_000339.3:c.1924C>T NP_000330.3:p.Arg642Cys missense NM_001126107.2:c.1921C>T NP_001119579.2:p.Arg641Cys missense NC_000016.10:g.56885363C>T NC_000016.9:g.56919275C>T NG_009386.2:g.25157C>T - Protein change
- R641C, R642C
- Other names
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- Canonical SPDI
- NC_000016.10:56885362:C:T
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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) 0.00007
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
- 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 | ||
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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
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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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 (1) |
criteria provided, single submitter
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Jan 29, 2024 | RCV001215299.5 | |
Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Jun 17, 2022 | RCV001833878.6 |
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
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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
(May 22, 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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3billion
Accession: SCV002521448.1
First in ClinVar: Jun 03, 2022 Last updated: Jun 03, 2022 |
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.012%). Missense changes are a common disease-causing mechanism. … (more)
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.012%). Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.53; 3Cnet: 1.00). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with SLC12A3 related disorder (ClinVar ID: VCV000944812 / PMID: 10561140). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PMID: 10561140, 15069170, 16370563). The variant has been reported to co-segregate with the disease in at least one similarly affected relative/individual in the same family or similarly affected unrelated family (PMID: 15069170). Different missense changes at the same codon (p.Arg642Gly, p.Arg642His) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000319909, VCV000397523). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Hypokalemia (present)
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Pathogenic
(Mar 01, 2022)
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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: SCV002785567.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Jun 17, 2022)
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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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Revvity Omics, Revvity
Accession: SCV003827919.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Pathogenic
(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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Invitae
Accession: SCV001387036.5
First in ClinVar: Jul 16, 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 642 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 642 of the SLC12A3 protein (p.Arg642Cys). This variant is present in population databases (rs200697179, gnomAD 0.07%). This missense change has been observed in individual(s) with Gitelman syndrome (PMID: 10561140, 15069170, 16370563, 21051746). 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. This variant is also known as c.1930C>T. ClinVar contains an entry for this variant (Variation ID: 944812). 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. This variant disrupts the p.Arg642 amino acid residue in SLC12A3. Other variant(s) that disrupt this residue have been observed in individuals with SLC12A3-related conditions (PMID: 12112667), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Apr 02, 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: SCV002089360.1
First in ClinVar: Feb 13, 2022 Last updated: Feb 13, 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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Recurrent deep intronic mutations in the SLC12A3 gene responsible for Gitelman's syndrome. | Lo YF | Clinical journal of the American Society of Nephrology : CJASN | 2011 | PMID: 21051746 |
Diagnosis of a case of Gitelman's syndrome based on renal clearance studies and gene analysis of a novel mutation of the thiazide-sensitive Na-Cl cotransporter. | Kageyama K | Journal of endocrinological investigation | 2005 | PMID: 16370563 |
Four novel mutations in the thiazide-sensitive Na-Cl co-transporter gene in Japanese patients with Gitelman's syndrome. | Maki N | Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association | 2004 | PMID: 15069170 |
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 |
Identification of a novel R642C mutation in Na/Cl cotransporter with Gitelman's syndrome. | Yahata K | American journal of kidney diseases : the official journal of the National Kidney Foundation | 1999 | PMID: 10561140 |
Text-mined citations for rs200697179 ...
HelpRecord last updated Mar 17, 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.