The best available variant frequency is uninformative because there are too few occurrences in population data. Statistically enriched in patients compared to ethnically matched controls. Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. The gain of a new splice site is predicted. Occurs in three or more cases with a recessive pathogenic variant in the same gene.
ClinVar Genomic variation as it relates to human health
NM_001126108.2(SLC12A3):c.626G>A (p.Arg209Gln)
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.
(6)
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
6
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.626G>A (p.Arg209Gln)
Variation ID: 805472 Accession: VCV000805472.13
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 16q13 16: 56870120 (GRCh38) [ NCBI UCSC ] 16: 56904032 (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 Jan 19, 2020 May 1, 2024 Nov 10, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001126108.2:c.626G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001119580.2:p.Arg209Gln missense NM_000339.3:c.626G>A NP_000330.3:p.Arg209Gln missense NM_001126107.2:c.623G>A NP_001119579.2:p.Arg208Gln missense NC_000016.10:g.56870120G>A NC_000016.9:g.56904032G>A NG_009386.2:g.9914G>A - Protein change
- R208Q, R209Q
- Other names
- -
- Canonical SPDI
- NC_000016.10:56870119: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.
-
The Genome Aggregation Database (gnomAD) 0.00004
Trans-Omics for Precision Medicine (TOPMed) 0.00004
- 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, multiple submitters, no conflicts
|
Nov 10, 2023 | RCV000993007.8 | |
|
SLC12A3-related disorder
|
Pathogenic (1) |
criteria provided, single submitter
|
Aug 9, 2023 | RCV003413782.4 |
| Pathogenic (1) |
criteria provided, single submitter
|
Jun 3, 2022 | RCV002549824.2 | |
| Pathogenic (2) |
criteria provided, single submitter
|
Jul 15, 2021 | RCV001807374.4 |
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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|---|---|---|---|---|---|
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Pathogenic
(Jun 19, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Athena Diagnostics
Accession: SCV001145680.1
First in ClinVar: Jan 19, 2020 Last updated: Jan 19, 2020 |
Comment:
The best available variant frequency is uninformative because there are too few occurrences in population data. Statistically enriched in patients compared to ethnically matched controls. … (more)
The best available variant frequency is uninformative because there are too few occurrences in population data. Statistically enriched in patients compared to ethnically matched controls. Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. The gain of a new splice site is predicted. Occurs in three or more cases with a recessive pathogenic variant in the same gene. (less)
|
|
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Pathogenic
(Nov 10, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001377369.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 209 of the SLC12A3 protein (p.Arg209Gln). … (more)
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 209 of the SLC12A3 protein (p.Arg209Gln). This variant is present in population databases (rs758035631, gnomAD 0.004%). This missense change has been observed in individuals with Gitelman syndrome (PMID: 11168953, 21415153, 23328711). ClinVar contains an entry for this variant (Variation ID: 805472). 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.Arg209 amino acid residue in SLC12A3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8528245, 11168953, 21415153). 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)
|
|
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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: SCV002055328.1
First in ClinVar: Jan 12, 2022 Last updated: Jan 12, 2022 |
|
|
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Pathogenic
(Aug 09, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
SLC12A3-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004115997.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The SLC12A3 c.626G>A variant is predicted to result in the amino acid substitution p.Arg209Gln. This variant has been reported along with a second plausibly disease … (more)
The SLC12A3 c.626G>A variant is predicted to result in the amino acid substitution p.Arg209Gln. This variant has been reported along with a second plausibly disease causing variant in several individuals with Gitelman syndrome (compound heterozygous phase is implied in these publications without evidence: Cruz et al 2001. PubMed ID: 11168953; Vargas-Poussou R et al 2011. PubMed ID: 21415153; Berry MR et al 2013. PubMed ID: 23328711; Walsh PR et al 2017. PubMed ID: 29942493). This variant is reported in 0.0040% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-56904032-G-A). A different substitution affecting the same codon (p.Arg209Trp) has also been reported to be pathogenic for Gitelman syndrome (see for example, Simon et al. 1996. PubMed ID: 8528245; Vargas-Poussou et al. 2011. PubMed ID: 21415153; Cruz et al. 2001. PubMed ID: 11168953). Taken together the c.626G>A (p.Arg209Gln) variant is interpreted as pathogenic. (less)
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Pathogenic
(Jun 03, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV003540207.2
First in ClinVar: Feb 07, 2023 Last updated: May 01, 2024 |
Comment:
The c.626G>A (p.R209Q) alteration is located in exon 5 (coding exon 5) of the SLC12A3 gene. This alteration results from a G to A substitution … (more)
The c.626G>A (p.R209Q) alteration is located in exon 5 (coding exon 5) of the SLC12A3 gene. This alteration results from a G to A substitution at nucleotide position 626, causing the arginine (R) at amino acid position 209 to be replaced by a glutamine (Q). Based on data from gnomAD, the A allele has an overall frequency of <0.0% (8/282586) total alleles studied. This alteration was detected in the homozygous state, and in conjunction with another alteration in SLC12A3, in multiple individuals with Gitelman syndrome (Ji, 2008; Vargas-Poussou, 2011; Glaudemans, 2012; Berry, 2013; Iqbal, 2016; Walsh, 2018; Hureaux, 2019; Cruz, 2020). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. (less)
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|
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Pathogenic
(Aug 12, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Gitelman syndrome
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV002089333.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
|
Comment:
Comment:
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 209 of the SLC12A3 protein (p.Arg209Gln). This variant is present in population databases (rs758035631, gnomAD 0.004%). This missense change has been observed in individuals with Gitelman syndrome (PMID: 11168953, 21415153, 23328711). ClinVar contains an entry for this variant (Variation ID: 805472). 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.Arg209 amino acid residue in SLC12A3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8528245, 11168953, 21415153). 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.
Comment:
The SLC12A3 c.626G>A variant is predicted to result in the amino acid substitution p.Arg209Gln. This variant has been reported along with a second plausibly disease causing variant in several individuals with Gitelman syndrome (compound heterozygous phase is implied in these publications without evidence: Cruz et al 2001. PubMed ID: 11168953; Vargas-Poussou R et al 2011. PubMed ID: 21415153; Berry MR et al 2013. PubMed ID: 23328711; Walsh PR et al 2017. PubMed ID: 29942493). This variant is reported in 0.0040% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-56904032-G-A). A different substitution affecting the same codon (p.Arg209Trp) has also been reported to be pathogenic for Gitelman syndrome (see for example, Simon et al. 1996. PubMed ID: 8528245; Vargas-Poussou et al. 2011. PubMed ID: 21415153; Cruz et al. 2001. PubMed ID: 11168953). Taken together the c.626G>A (p.Arg209Gln) variant is interpreted as pathogenic.
Comment:
The c.626G>A (p.R209Q) alteration is located in exon 5 (coding exon 5) of the SLC12A3 gene. This alteration results from a G to A substitution at nucleotide position 626, causing the arginine (R) at amino acid position 209 to be replaced by a glutamine (Q). Based on data from gnomAD, the A allele has an overall frequency of <0.0% (8/282586) total alleles studied. This alteration was detected in the homozygous state, and in conjunction with another alteration in SLC12A3, in multiple individuals with Gitelman syndrome (Ji, 2008; Vargas-Poussou, 2011; Glaudemans, 2012; Berry, 2013; Iqbal, 2016; Walsh, 2018; Hureaux, 2019; Cruz, 2020). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is 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:
The best available variant frequency is uninformative because there are too few occurrences in population data. Statistically enriched in patients compared to ethnically matched controls. Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. The gain of a new splice site is predicted. Occurs in three or more cases with a recessive pathogenic variant in the same gene.
Comment:
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 209 of the SLC12A3 protein (p.Arg209Gln). This variant is present in population databases (rs758035631, gnomAD 0.004%). This missense change has been observed in individuals with Gitelman syndrome (PMID: 11168953, 21415153, 23328711). ClinVar contains an entry for this variant (Variation ID: 805472). 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.Arg209 amino acid residue in SLC12A3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8528245, 11168953, 21415153). 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.
Comment:
The SLC12A3 c.626G>A variant is predicted to result in the amino acid substitution p.Arg209Gln. This variant has been reported along with a second plausibly disease causing variant in several individuals with Gitelman syndrome (compound heterozygous phase is implied in these publications without evidence: Cruz et al 2001. PubMed ID: 11168953; Vargas-Poussou R et al 2011. PubMed ID: 21415153; Berry MR et al 2013. PubMed ID: 23328711; Walsh PR et al 2017. PubMed ID: 29942493). This variant is reported in 0.0040% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-56904032-G-A). A different substitution affecting the same codon (p.Arg209Trp) has also been reported to be pathogenic for Gitelman syndrome (see for example, Simon et al. 1996. PubMed ID: 8528245; Vargas-Poussou et al. 2011. PubMed ID: 21415153; Cruz et al. 2001. PubMed ID: 11168953). Taken together the c.626G>A (p.Arg209Gln) variant is interpreted as pathogenic.
Comment:
The c.626G>A (p.R209Q) alteration is located in exon 5 (coding exon 5) of the SLC12A3 gene. This alteration results from a G to A substitution at nucleotide position 626, causing the arginine (R) at amino acid position 209 to be replaced by a glutamine (Q). Based on data from gnomAD, the A allele has an overall frequency of <0.0% (8/282586) total alleles studied. This alteration was detected in the homozygous state, and in conjunction with another alteration in SLC12A3, in multiple individuals with Gitelman syndrome (Ji, 2008; Vargas-Poussou, 2011; Glaudemans, 2012; Berry, 2013; Iqbal, 2016; Walsh, 2018; Hureaux, 2019; Cruz, 2020). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| High-throughput sequencing contributes to the diagnosis of tubulopathies and familial hypercalcemia hypocalciuria in adults. | Hureaux M | Kidney international | 2019 | PMID: 31672324 |
| Clinical and diagnostic features of Bartter and Gitelman syndromes. | Walsh PR | Clinical kidney journal | 2018 | PMID: 29942493 |
| Case Report: Cervical chondrocalcinosis as a complication of Gitelman syndrome. | Iqbal Z | F1000Research | 2016 | PMID: 27303630 |
| 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 |
| Spectrum of mutations in Gitelman syndrome. | Vargas-Poussou R | Journal of the American Society of Nephrology : JASN | 2011 | PMID: 21415153 |
| Rare independent mutations in renal salt handling genes contribute to blood pressure variation. | Ji W | Nature genetics | 2008 | PMID: 18391953 |
| Gitelman's syndrome revisited: an evaluation of symptoms and health-related quality of life. | Cruz DN | Kidney international | 2001 | PMID: 11168953 |
| Gitelman's variant of Bartter's syndrome, inherited hypokalaemic alkalosis, is caused by mutations in the thiazide-sensitive Na-Cl cotransporter. | Simon DB | Nature genetics | 1996 | PMID: 8528245 |
Text-mined citations for rs758035631 ...
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.