ClinVar Genomic variation as it relates to human health
NM_000085.5(CLCNKB):c.1312C>T (p.Arg438Cys)
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(3); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000085.5(CLCNKB):c.1312C>T (p.Arg438Cys)
Variation ID: 7593 Accession: VCV000007593.6
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1p36.13 1: 16051724 (GRCh38) [ NCBI UCSC ] 1: 16378219 (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 Sep 3, 2013 Apr 6, 2024 Mar 29, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000085.5:c.1312C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000076.2:p.Arg438Cys missense NM_001165945.2:c.805C>T NP_001159417.2:p.Arg269Cys missense NC_000001.11:g.16051724C>T NC_000001.10:g.16378219C>T NG_013079.1:g.12973C>T NG_042865.1:g.7232C>T P51801:p.Arg438Cys - Protein change
- R438C, R269C
- Other names
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- Canonical SPDI
- NC_000001.11:16051723: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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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) 0.00008
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
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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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CLCNKB | - | - |
GRCh38 GRCh37 |
27 | 525 | |
LOC106501713 | - | - | - | GRCh38 | - | 483 |
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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Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Mar 29, 2024 | RCV000008031.4 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jun 27, 2022 | RCV000054563.5 |
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
(May 10, 2018)
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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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Athena Diagnostics
Accession: SCV000841582.1
First in ClinVar: Sep 03, 2013 Last updated: Sep 03, 2013 |
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Pathogenic
(Jun 27, 2022)
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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: SCV002233076.2
First in ClinVar: Mar 28, 2022 Last updated: Feb 07, 2023 |
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 438 of the CLCNKB protein … (more)
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 438 of the CLCNKB protein (p.Arg438Cys). This variant is present in population databases (rs121909133, gnomAD 0.007%). This missense change has been observed in individuals with Bartter syndrome (PMID: 9326936, 21631963, 28381550, 31115572). ClinVar contains an entry for this variant (Variation ID: 7593). 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 CLCNKB protein function. Experimental studies have shown that this missense change affects CLCNKB function (PMID: 10831588, 11734858). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant disrupts the p.Arg438 amino acid residue in CLCNKB. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10906158, 23703872, 28381550, 31115572, 32857947). 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
(Mar 29, 2024)
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criteria provided, single submitter
Method: clinical testing
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Bartter disease type 3
Affected status: unknown
Allele origin:
germline
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Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004807576.1
First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024 |
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Uncertain significance
(Aug 31, 2018)
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criteria provided, single submitter
Method: research
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Bartter disease type 3
Affected status: yes
Allele origin:
unknown
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HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology
Study: CSER-SouthSeq
Accession: SCV000891757.1 First in ClinVar: Jan 06, 2017 Last updated: Jan 06, 2017 |
Comment:
ACMG codes: PM2, PP3, PP4
Number of individuals with the variant: 1
Clinical Features:
Intrauterine growth retardation (present) , Limb hypertonia (present) , Hydronephrosis (present) , Renal tubular dysfunction (present) , Butterfly vertebrae (present) , Hyperglycemia (present) , Abnormal … (more)
Intrauterine growth retardation (present) , Limb hypertonia (present) , Hydronephrosis (present) , Renal tubular dysfunction (present) , Butterfly vertebrae (present) , Hyperglycemia (present) , Abnormal vertebral morphology (present) , Hyponatremia (present) (less)
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Pathogenic
(Oct 01, 1997)
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no assertion criteria provided
Method: literature only
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BARTTER SYNDROME, TYPE 3
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000028236.2
First in ClinVar: Apr 04, 2013 Last updated: Jan 06, 2017 |
Comment on evidence:
One of the missense mutations in the CLCNKB gene identified by Simon et al. (1997) in classic Bartter syndrome (BARTS3; 607364) patients was arg438 to … (more)
One of the missense mutations in the CLCNKB gene identified by Simon et al. (1997) in classic Bartter syndrome (BARTS3; 607364) patients was arg438 to cys (R438C), where R438 is conserved among all members of the CLC family. (less)
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unknown
(-)
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no assertion criteria provided
Method: not provided
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not provided
Affected status: not provided
Allele origin:
unknown
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Martin Pollak Laboratory, Beth Israel Deaconess Medical Center
Accession: SCV000077253.1
First in ClinVar: Sep 03, 2013 Last updated: Sep 03, 2013
Comment:
Lower UCa2+ group
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Comment:
Converted during submission to Uncertain significance.
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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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Bartter syndrome with long-term follow-up: a case report. | Wu X | The Journal of international medical research | 2020 | PMID: 32857947 |
A novel mutation associated with Type III Bartter syndrome: A report of five cases. | Li Y | Molecular medicine reports | 2019 | PMID: 31115572 |
Clinical and Genetic Spectrum of Bartter Syndrome Type 3. | Seys E | Journal of the American Society of Nephrology : JASN | 2017 | PMID: 28381550 |
ClC-K chloride channels: emerging pathophysiology of Bartter syndrome type 3. | Andrini O | American journal of physiology. Renal physiology | 2015 | PMID: 25810436 |
Frequency of rare allelic variation in candidate genes among individuals with low and high urinary calcium excretion. | Toka HR | PloS one | 2013 | PMID: 23991001 |
Novel CLCNKB mutations causing Bartter syndrome affect channel surface expression. | Keck M | Human mutation | 2013 | PMID: 23703872 |
DNA analysis of renal electrolyte transporter genes among patients suffering from Bartter and Gitelman syndromes: summary of mutation screening. | Urbanová M | Folia biologica | 2011 | PMID: 21631963 |
Barttin is a Cl- channel beta-subunit crucial for renal Cl- reabsorption and inner ear K+ secretion. | Estévez R | Nature | 2001 | PMID: 11734858 |
Mutations in the chloride channel gene CLCNKB as a cause of classic Bartter syndrome. | Konrad M | Journal of the American Society of Nephrology : JASN | 2000 | PMID: 10906158 |
Functional and structural analysis of ClC-K chloride channels involved in renal disease. | Waldegger S | The Journal of biological chemistry | 2000 | PMID: 10831588 |
Mutations in the chloride channel gene, CLCNKB, cause Bartter's syndrome type III. | Simon DB | Nature genetics | 1997 | PMID: 9326936 |
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Text-mined citations for rs121909133 ...
HelpRecord last updated May 08, 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.