ClinVar Genomic variation as it relates to human health
NM_153766.3(KCNJ1):c.601C>T (p.Leu201Phe)
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); Likely pathogenic(1); Uncertain significance(2)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_153766.3(KCNJ1):c.601C>T (p.Leu201Phe)
Variation ID: 872043 Accession: VCV000872043.39
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11q24.3 11: 128839643 (GRCh38) [ NCBI UCSC ] 11: 128709538 (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 May 12, 2020 May 12, 2024 Mar 29, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_153766.3:c.601C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_722450.1:p.Leu201Phe missense NM_000220.5:c.658C>T NM_000220.6:c.658C>T NP_000211.1:p.Leu220Phe missense NM_153764.3:c.601C>T NP_722448.1:p.Leu201Phe missense NM_153765.3:c.652C>T NP_722449.3:p.Leu218Phe missense NM_153766.2:c.601C>T NM_153767.4:c.601C>T NP_722451.1:p.Leu201Phe missense NC_000011.10:g.128839643G>A NC_000011.9:g.128709538G>A NG_009379.1:g.32731C>T - Protein change
- L218F, L220F, L201F
- Other names
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- Canonical SPDI
- NC_000011.10:128839642: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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0.00040 (A)
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Allele frequency
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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
1000 Genomes Project 30x 0.00031
The Genome Aggregation Database (gnomAD), exomes 0.00036
Exome Aggregation Consortium (ExAC) 0.00039
1000 Genomes Project 0.00040
- 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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KCNJ1 | - | - |
GRCh38 GRCh37 |
258 | 343 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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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Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Jan 18, 2024 | RCV001092303.25 | |
Conflicting interpretations of pathogenicity (8) |
criteria provided, conflicting classifications
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Mar 29, 2024 | RCV001251500.14 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 3, 2022 | RCV002282455.2 |
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 22, 2022)
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criteria provided, single submitter
Method: clinical testing
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Bartter disease type 2
Affected status: yes
Allele origin:
germline
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3billion
Accession: SCV002521404.1
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: 0.036%). 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: 0.036%). Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.69; 3Cnet: 0.07). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000872043). A different missense change at the same codon (p.Leu201Arg) has been reported to be associated with KCNJ1 related disorder (ClinVar ID: VCV000870375 / PMID: 32573669). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Renal tubular dysfunction (present)
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Pathogenic
(Jun 24, 2022)
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criteria provided, single submitter
Method: clinical testing
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Bartter disease type 2
(Autosomal recessive inheritance)
Affected status: no
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV001427117.3
First in ClinVar: Aug 13, 2020 Last updated: Jul 23, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Bartter syndrome, type 2 (MIM#241200). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from leucine to phenylalanine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (87 heterozygote(s), 1 homozygote). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated IRK potassium channel domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported several times as pathogenic, and observed in homozygous and compound heterozygous individuals with Bartter syndrome (ClinVar, PMID: 29942493, PMID: 24659592, PMID: 32997650, PMID: 24400161). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Xenopus oocytes demonstrating impaired channel activity resulting in the reduction of potassium currents (PMID: 24400161). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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Pathogenic
(Aug 03, 2022)
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criteria provided, single submitter
Method: clinical testing
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Bartter syndrome
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002572306.1
First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022 |
Comment:
Variant summary: KCNJ1 c.658C>T (p.Leu220Phe) results in a non-conservative amino acid change located in the C-terminal domain (IPR041647) of the encoded protein sequence. Four of … (more)
Variant summary: KCNJ1 c.658C>T (p.Leu220Phe) results in a non-conservative amino acid change located in the C-terminal domain (IPR041647) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00036 in 249254 control chromosomes, predominantly at a frequency of 0.0024 within the South Asian subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 2-fold of the estimated maximal expected allele frequency for a pathogenic variant in KCNJ1 causing Bartter Syndrome, Type 2 phenotype (0.0011), suggesting that the variant might be a benign polymorphism. However, the variant c.658C>T, has also been reported in the literature in compound heterozygous and homozygous state, in individuals (mostly of South Asian or Middle Eastern origin) who were affected with Bartter Syndrome, Type 2, where homozygotes were described to have a milder, adult onset phenotype (e.g. Vollmer_1998, Kunzelmann_2000, Srivastava_2013, Sharma_2014, Huang_2014, Jayasinghe_2021, Elfert_2020). These data indicate that the variant is very likely to be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function, and while an early in vitro study demonstrated no major functional impact (Kunzelmann_2000), a later study described a partial loss of function when the L220F variant was expressed alone (i.e. mimicking a homozygous state), while it almost completely abolished channel activity when co-expressed together with another variant (S219R, i.e. mimicking a compound heterozygous state), in addition, the variant also affected phosphatidylinositol 4,5-bisphosphate (PIP2)-dependent gating of the channel (Srivastava_2013). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and all laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant likely represents a hypomorphic allele, resulting in an attenuated phenotype in homozygotes, therefore it was classified as pathogenic. (less)
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Likely pathogenic
(May 07, 2022)
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criteria provided, single submitter
Method: clinical testing
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Bartter disease type 2
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002811629.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Uncertain significance
(Mar 01, 2023)
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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: SCV003840615.1
First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023 |
Comment:
Published functional studies suggest a damaging effect (Peters et al., 2003; Srivastava et al., 2013); In silico analysis supports that this missense variant does not … (more)
Published functional studies suggest a damaging effect (Peters et al., 2003; Srivastava et al., 2013); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24696311, 10878442, 12911542, 10611379, 34426522, 32997650, 24400161, 9502574, 32939031, 24659592, 35195872, 29942493) (less)
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Pathogenic
(Oct 10, 2023)
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criteria provided, single submitter
Method: clinical testing
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Bartter disease type 2
(Autosomal recessive inheritance)
Affected status: no
Allele origin:
germline
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Intergen, Intergen Genetics and Rare Diseases Diagnosis Center
Accession: SCV004041601.1
First in ClinVar: Oct 14, 2023 Last updated: Oct 14, 2023 |
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Pathogenic
(Oct 28, 2023)
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criteria provided, single submitter
Method: clinical testing
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Bartter disease type 2
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital
Accession: SCV004099282.1
First in ClinVar: Nov 04, 2023 Last updated: Nov 04, 2023 |
Comment:
This heterozygous mis-sense variant is identified in a 5 year malewith polyurea, hypokalemia, GDD, dandy walker malformation, nephrocalcinosis and optic disc hypoplasia. This nucleotide change … (more)
This heterozygous mis-sense variant is identified in a 5 year malewith polyurea, hypokalemia, GDD, dandy walker malformation, nephrocalcinosis and optic disc hypoplasia. This nucleotide change is present in gnomAD database with a low allele frequency 0.0357% [PM2]. Insilico prediction [REVEL=0.71] predicts deleterious nature of this variant [PP3]. The variant is identified in trans [PM3] with another variant p.Thr191Pro. A clinvar entry for this variant is available. This variant is submitted to clinvar database [Variation ID: 7116] with “Conflicting interpretation of pathogenecity”, [Pathogenic (7), Likely Pathogenic (1), Uncertain Significance (1)” by multiple submitters [PP5]. Based on the clinical correlation and available evidence, this variant is classified as "Pathogenic". (less)
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Bartter disease type 2
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV004171899.1
First in ClinVar: Dec 09, 2023 Last updated: Dec 09, 2023 |
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Pathogenic
(Oct 26, 2023)
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criteria provided, single submitter
Method: clinical testing
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Bartter disease type 2
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV003820863.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 18, 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: SCV002242769.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 220 of the KCNJ1 protein (p.Leu220Phe). … (more)
This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 220 of the KCNJ1 protein (p.Leu220Phe). This variant is present in population databases (rs200320892, gnomAD 0.2%). This missense change has been observed in individuals with Bartter syndrome (PMID: 9502574, 10611379, 24400161, 24659592, 24696311, 29942493). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 872043). 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. Experimental studies have shown that this missense change affects KCNJ1 function (PMID: 10611379, 12911542, 24400161). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Oct 01, 2021)
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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: SCV001248736.21
First in ClinVar: May 12, 2020 Last updated: May 12, 2024 |
Number of individuals with the variant: 4
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Uncertain significance
(Mar 29, 2024)
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criteria provided, single submitter
Method: clinical testing
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Bartter disease type 2
Affected status: unknown
Allele origin:
germline
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Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004808196.1
First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024 |
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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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Clinical impact of genomic testing in patients with suspected monogenic kidney disease. | Jayasinghe K | Genetics in medicine : official journal of the American College of Medical Genetics | 2021 | PMID: 32939031 |
Late-Onset Bartter Syndrome Type II Due to a Homozygous Mutation in KCNJ1 Gene: A Case Report and Literature Review. | Elfert KA | The American journal of case reports | 2020 | PMID: 32997650 |
Feasibility of Ultra-Rapid Exome Sequencing in Critically Ill Infants and Children With Suspected Monogenic Conditions in the Australian Public Health Care System. | Australian Genomics Health Alliance Acute Care Flagship | JAMA | 2020 | PMID: 32573669 |
Clinical and diagnostic features of Bartter and Gitelman syndromes. | Walsh PR | Clinical kidney journal | 2018 | PMID: 29942493 |
Genetic analysis in Bartter syndrome from India. | Sharma PK | Indian journal of pediatrics | 2014 | PMID: 24696311 |
Nephrocalcinosis as adult presentation of Bartter syndrome type II. | Huang L | The Netherlands journal of medicine | 2014 | PMID: 24659592 |
Identification of compound heterozygous KCNJ1 mutations (encoding ROMK) in a kindred with Bartter's syndrome and a functional analysis of their pathogenicity. | Srivastava S | Physiological reports | 2013 | PMID: 24400161 |
Classification and rescue of ROMK mutations underlying hyperprostaglandin E syndrome/antenatal Bartter syndrome. | Peters M | Kidney international | 2003 | PMID: 12911542 |
A Bartter's syndrome mutation of ROMK1 exerts dominant negative effects on K(+) conductance. | Kunzelmann K | Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology | 2000 | PMID: 10878442 |
pH gating of ROMK (K(ir)1.1) channels: control by an Arg-Lys-Arg triad disrupted in antenatal Bartter syndrome. | Schulte U | Proceedings of the National Academy of Sciences of the United States of America | 1999 | PMID: 10611379 |
Two novel mutations of the gene for Kir 1.1 (ROMK) in neonatal Bartter syndrome. | Vollmer M | Pediatric nephrology (Berlin, Germany) | 1998 | PMID: 9502574 |
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Text-mined citations for rs200320892 ...
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.