ACMG criteria used:PS3, PS4, PM1, PM2, PM3, PP3, PP5
ClinVar Genomic variation as it relates to human health
NM_001126108.2(SLC12A3):c.2191G>A (p.Gly731Arg)
Germline
Classification
Help
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.
(7)
Help
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.
Pathogenic/Likely pathogenic
7
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_001126108.2(SLC12A3):c.2191G>A (p.Gly731Arg)
Variation ID: 562347 Accession: VCV000562347.15
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 16q13 16: 56887937 (GRCh38) [ NCBI UCSC ] 16: 56921849 (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 Oct 1, 2018 Feb 14, 2024 Dec 14, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001126108.2:c.2191G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001119580.2:p.Gly731Arg missense NM_000339.3:c.2191G>A NP_000330.3:p.Gly731Arg missense NM_001126107.2:c.2188G>A NP_001119579.2:p.Gly730Arg missense NC_000016.10:g.56887937G>A NC_000016.9:g.56921849G>A NG_009386.1:g.27731G>A - Protein change
- G731R, G730R
- Other names
- -
- Canonical SPDI
- NC_000016.10:56887936:G:A
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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.
-
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00002
The Genome Aggregation Database (gnomAD) 0.00005
Trans-Omics for Precision Medicine (TOPMed) 0.00006
- 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 |
1632 | 1726 | |
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 (2) |
criteria provided, single submitter
|
Dec 14, 2023 | RCV000681801.7 | |
| Pathogenic/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Apr 27, 2022 | RCV000762974.11 |
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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|---|---|---|---|---|---|
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Pathogenic
(Jul 15, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Familial hypokalemia-hypomagnesemia
Affected status: no
Allele origin:
germline
|
Genome-Nilou Lab
Accession: SCV002055348.1
First in ClinVar: Jan 12, 2022 Last updated: Jan 12, 2022 |
|
|
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Pathogenic
(Apr 27, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Familial hypokalemia-hypomagnesemia
Affected status: yes
Allele origin:
germline
|
European Hospital Georges Pompidou Genetics Department, Assistance Publique - Hôpitaux de Paris AP-HP
Accession: SCV002513815.1
First in ClinVar: May 21, 2022 Last updated: May 21, 2022
Comment:
ACMG criteria used:PS3, PS4, PM1, PM2, PM3, PP3, PP5
|
Comment:
ACMG criteria used:PS3, PS4, PM1, PM2, PM3, PP3, PP5
|
|
|
Pathogenic
(Mar 09, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Familial hypokalemia-hypomagnesemia
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV000893417.2
First in ClinVar: Mar 31, 2019 Last updated: Dec 31, 2022 |
|
|
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Likely pathogenic
(Apr 13, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Familial hypokalemia-hypomagnesemia
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Division Of Personalized Genomic Medicine, Columbia University Irving Medical Center
Accession: SCV004190151.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
Comment:
The c.2191G>A variant in the SLC12A3 gene is a heterozygous missense variant, which results in the substitution of the highly conserved glycine residue at the … (more)
The c.2191G>A variant in the SLC12A3 gene is a heterozygous missense variant, which results in the substitution of the highly conserved glycine residue at the 731 position to arginine (p.Gly731Arg). This variant localizes to coding exon 18 of the SLC12A3 gene (26 exons total; NM_000339.3). This variant is predicted to be deleterious and damaging to protein structure and/or function based on in silico analyses (PROVEAN and SIFT). This variant has been observed in the Genome Aggregation Database (gnomAD) at a very low frequency (allele frequency = 0.00002837, no homozygotes), indicating it is not a common benign variant in the populations represented in this database. This variant has been reported in multiple individuals with Gitelman syndrome either in the homozygous state or with another SLC12A3 variant (PMIDs: 17699451, 21415153, 30596175, 25422309). (less)
Clinical Features:
Hypokalemia (present)
Age: 30-39 years
Sex: female
Comment on evidence:
Observed in trans with c.1844C>T
|
|
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Pathogenic
(Dec 14, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001202771.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 731 of the SLC12A3 protein (p.Gly731Arg). … (more)
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 731 of the SLC12A3 protein (p.Gly731Arg). This variant is present in population databases (rs752101663, gnomAD 0.004%). This missense change has been observed in individual(s) with Gitelman syndrome (PMID: 8900229, 12112667, 21415153, 25422309). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 562347). 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%. Experimental studies have shown that this missense change affects SLC12A3 function (PMID: 27582097). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
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Likely pathogenic
(Sep 16, 2018)
|
no assertion criteria provided
Method: research
|
not provided
Affected status: yes
Allele origin:
germline
|
Gharavi Laboratory, Columbia University
Accession: SCV000809268.1
First in ClinVar: Oct 01, 2018 Last updated: Oct 01, 2018 |
|
|
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Pathogenic
(Sep 30, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Gitelman syndrome
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV002089371.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
|
Comment:
Comment:
The c.2191G>A variant in the SLC12A3 gene is a heterozygous missense variant, which results in the substitution of the highly conserved glycine residue at the 731 position to arginine (p.Gly731Arg). This variant localizes to coding exon 18 of the SLC12A3 gene (26 exons total; NM_000339.3). This variant is predicted to be deleterious and damaging to protein structure and/or function based on in silico analyses (PROVEAN and SIFT). This variant has been observed in the Genome Aggregation Database (gnomAD) at a very low frequency (allele frequency = 0.00002837, no homozygotes), indicating it is not a common benign variant in the populations represented in this database. This variant has been reported in multiple individuals with Gitelman syndrome either in the homozygous state or with another SLC12A3 variant (PMIDs: 17699451, 21415153, 30596175, 25422309).
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 731 of the SLC12A3 protein (p.Gly731Arg). This variant is present in population databases (rs752101663, gnomAD 0.004%). This missense change has been observed in individual(s) with Gitelman syndrome (PMID: 8900229, 12112667, 21415153, 25422309). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 562347). 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%. Experimental studies have shown that this missense change affects SLC12A3 function (PMID: 27582097). For these reasons, this variant has been classified as Pathogenic.
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. |
Comment:
ACMG criteria used:PS3, PS4, PM1, PM2, PM3, PP3, PP5
Comment:
The c.2191G>A variant in the SLC12A3 gene is a heterozygous missense variant, which results in the substitution of the highly conserved glycine residue at the 731 position to arginine (p.Gly731Arg). This variant localizes to coding exon 18 of the SLC12A3 gene (26 exons total; NM_000339.3). This variant is predicted to be deleterious and damaging to protein structure and/or function based on in silico analyses (PROVEAN and SIFT). This variant has been observed in the Genome Aggregation Database (gnomAD) at a very low frequency (allele frequency = 0.00002837, no homozygotes), indicating it is not a common benign variant in the populations represented in this database. This variant has been reported in multiple individuals with Gitelman syndrome either in the homozygous state or with another SLC12A3 variant (PMIDs: 17699451, 21415153, 30596175, 25422309).
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 731 of the SLC12A3 protein (p.Gly731Arg). This variant is present in population databases (rs752101663, gnomAD 0.004%). This missense change has been observed in individual(s) with Gitelman syndrome (PMID: 8900229, 12112667, 21415153, 25422309). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 562347). 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%. Experimental studies have shown that this missense change affects SLC12A3 function (PMID: 27582097). For these reasons, this variant has been classified as Pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Clinical and Genetic Characteristics in Patients With Gitelman Syndrome. | Fujimura J | Kidney international reports | 2018 | PMID: 30596175 |
| Functionomics of NCC mutations in Gitelman syndrome using a novel mammalian cell-based activity assay. | Valdez-Flores MA | American journal of physiology. Renal physiology | 2016 | PMID: 27582097 |
| 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 |
| Spectrum of mutations in Gitelman syndrome. | Vargas-Poussou R | Journal of the American Society of Nephrology : JASN | 2011 | PMID: 21415153 |
| A thiazide test for the diagnosis of renal tubular hypokalemic disorders. | Colussi G | Clinical journal of the American Society of Nephrology : CJASN | 2007 | PMID: 17699451 |
| 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 |
| Novel molecular variants of the Na-Cl cotransporter gene are responsible for Gitelman syndrome. | Mastroianni N | American journal of human genetics | 1996 | PMID: 8900229 |
Text-mined citations for rs752101663 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record 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.