ClinVar Genomic variation as it relates to human health
NM_001126108.2(SLC12A3):c.2954G>A (p.Cys985Tyr)
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.
Pathogenic(9); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001126108.2(SLC12A3):c.2954G>A (p.Cys985Tyr)
Variation ID: 448395 Accession: VCV000448395.44
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 16q13 16: 56913293 (GRCh38) [ NCBI UCSC ] 16: 56947205 (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 Dec 19, 2017 May 12, 2024 Jan 29, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001126108.2:c.2954G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001119580.2:p.Cys985Tyr missense NM_000339.3:c.2981G>A NP_000330.3:p.Cys994Tyr missense NM_001126107.2:c.2978G>A NP_001119579.2:p.Cys993Tyr missense NC_000016.10:g.56913293G>A NC_000016.9:g.56947205G>A NG_009386.1:g.53087G>A - Protein change
- C994Y, C993Y, C985Y
- Other names
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- Canonical SPDI
- NC_000016.10:56913292:G:A
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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 (A)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
The Genome Aggregation Database (gnomAD) 0.00008
Trans-Omics for Precision Medicine (TOPMed) 0.00012
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
The Genome Aggregation Database (gnomAD), exomes 0.00020
Exome Aggregation Consortium (ExAC) 0.00025
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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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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LOC126862361 | - | - | - | GRCh38 | - | 68 |
SLC12A3 | - | - |
GRCh38 GRCh37 |
1590 | 1681 |
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 (4) |
criteria provided, multiple submitters, no conflicts
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Jan 29, 2024 | RCV000517299.28 | |
Conflicting interpretations of pathogenicity (7) |
criteria provided, conflicting classifications
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Jan 27, 2023 | RCV001271446.20 |
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
(Jun 30, 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: SCV001752474.1
First in ClinVar: Jul 18, 2021 Last updated: Jul 18, 2021
Comment:
This variant has been detected in individual(s) who were sent for testing of Renasight - kidney gene panel.
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Pathogenic
(Oct 09, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Athena Diagnostics
Accession: SCV000615291.2
First in ClinVar: Dec 19, 2017 Last updated: Sep 19, 2021 |
Comment:
The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant is statistically more frequent in affected individuals than in … (more)
The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant is statistically more frequent in affected individuals than in the general population and/or healthy controls. This variant is also referred to as Cys985Tyr in published literature. Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant is shown to impair SLC12A3 protein trafficking to the plasma membrane (PMID 12039972). In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. (less)
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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: SCV002055359.1
First in ClinVar: Jan 12, 2022 Last updated: Jan 12, 2022 |
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Uncertain significance
(Nov 11, 2021)
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criteria provided, single submitter
Method: clinical testing
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Familial hypokalemia-hypomagnesemia
Affected status: yes
Allele origin:
inherited
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Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn
Accession: SCV002103054.1
First in ClinVar: Mar 12, 2022 Last updated: Mar 12, 2022 |
Comment:
PS3_moderate, PS4_moderate
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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: SCV002513829.1
First in ClinVar: May 21, 2022 Last updated: May 21, 2022
Comment:
ACMG criteria used:PS4 PS3 PM1 PM2 PM3 PP3 PP5
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Comment:
ACMG criteria used:PS4 PS3 PM1 PM2 PM3 PP3 PP5
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Pathogenic
(Dec 01, 2022)
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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: SCV001766181.2
First in ClinVar: Aug 07, 2021 Last updated: Dec 11, 2022 |
Comment:
Published functional studies demonstrate a damaging effect in Xenopus oocytes (De Jong et al., 2002); In silico analysis supports that this missense variant has a … (more)
Published functional studies demonstrate a damaging effect in Xenopus oocytes (De Jong et al., 2002); 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, 23328711, 17654016, 20675610, 21415153, 25422309, 22990302, 22009145, 21753071, 27216017, 12039972, 30136149, 31672324, 31589614, 35591852, 34389731, 34860177) (less)
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Pathogenic
(Jan 27, 2023)
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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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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV003800734.2
First in ClinVar: Feb 13, 2023 Last updated: Nov 11, 2023 |
Comment:
Variant summary: SLC12A3 c.2981G>A (p.Cys994Tyr) results in a non-conservative amino acid change located in the SLC12A transporter, C-terminal domain (IPR018491) of the encoded protein sequence. … (more)
Variant summary: SLC12A3 c.2981G>A (p.Cys994Tyr) results in a non-conservative amino acid change located in the SLC12A transporter, C-terminal domain (IPR018491) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0002 in 251292 control chromosomes. This frequency does not allow conclusions about variant significance. c.2981G>A has been reported in the literature as a biallelic genotype in multiple individuals affected with Familial Hypokalemia-Hypomagnesemia (Gitelman Syndrome) (example, PMID: 22009145, 29398133). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (example, PMID: 12039972), demonstrating significantly reduced metolazone-sensitive (22)Na(+) uptake relative to the wild-type thereby impacting functional outcomes. Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 (Pathogenic, n=9). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Aug 30, 2021)
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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: SCV002020626.3
First in ClinVar: Nov 29, 2021 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: SCV001202063.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 994 of the SLC12A3 protein … (more)
This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 994 of the SLC12A3 protein (p.Cys994Tyr). This variant is present in population databases (rs199849117, gnomAD 0.03%). This missense change has been observed in individual(s) with Gitelman syndrome (PMID: 12112667, 21415153, 22009145, 23328711, 25422309). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as p.Cys985Tyr. ClinVar contains an entry for this variant (Variation ID: 448395). 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: 12039972). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Dec 01, 2020)
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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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001500079.18
First in ClinVar: Mar 14, 2021 Last updated: May 12, 2024 |
Number of individuals with the variant: 1
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Pathogenic
(Sep 16, 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: SCV001452599.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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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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Simultaneous sequencing of 37 genes identified causative mutations in the majority of children with renal tubulopathies. | Ashton EJ | Kidney international | 2018 | PMID: 29398133 |
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 |
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 |
Renal phosphate handling in Gitelman syndrome--the results of a case-control study. | Viganò C | Pediatric nephrology (Berlin, Germany) | 2013 | PMID: 22990302 |
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 |
Phenotype-genotype correlation and follow-up in adult patients with hypokalaemia of renal origin suggesting Gitelman syndrome. | Balavoine AS | European journal of endocrinology | 2011 | PMID: 21753071 |
Spectrum of mutations in Gitelman syndrome. | Vargas-Poussou R | Journal of the American Society of Nephrology : JASN | 2011 | PMID: 21415153 |
Novel mutations in the SLC12A3 gene causing Gitelman's syndrome in Swedes. | Fava C | DNA sequence : the journal of DNA sequencing and mapping | 2007 | PMID: 17654016 |
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 |
Functional expression of mutations in the human NaCl cotransporter: evidence for impaired routing mechanisms in Gitelman's syndrome. | De Jong JC | Journal of the American Society of Nephrology : JASN | 2002 | PMID: 12039972 |
Text-mined citations for rs199849117 ...
HelpRecord last updated May 12, 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.