ClinVar Genomic variation as it relates to human health
NM_000891.3(KCNJ2):c.119G>A (p.Arg40Gln)
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.
Uncertain significance(8); Benign(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000891.3(KCNJ2):c.119G>A (p.Arg40Gln)
Variation ID: 324830 Accession: VCV000324830.18
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 17q24.3 17: 70175158 (GRCh38) [ NCBI UCSC ] 17: 68171299 (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 Dec 6, 2016 May 1, 2024 Jan 29, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000891.3:c.119G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000882.1:p.Arg40Gln missense NC_000017.11:g.70175158G>A NC_000017.10:g.68171299G>A NG_008798.1:g.10624G>A LRG_328:g.10624G>A LRG_328t1:c.119G>A LRG_328p1:p.Arg40Gln - Protein change
- R40Q
- Other names
- -
- Canonical SPDI
- NC_000017.11:70175157:G:A
-
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
Trans-Omics for Precision Medicine (TOPMed) 0.00003
The Genome Aggregation Database (gnomAD) 0.00004
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. |
|||
KCNJ2 | - | - |
GRCh38 GRCh37 |
577 | 600 |
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. |
---|---|---|---|---|
Uncertain significance (1) |
criteria provided, single submitter
|
Jan 12, 2018 | RCV000308982.5 | |
Uncertain significance (1) |
criteria provided, single submitter
|
Jan 12, 2018 | RCV000347359.5 | |
Uncertain significance (1) |
criteria provided, single submitter
|
Jan 12, 2018 | RCV000406881.5 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
|
Mar 8, 2022 | RCV000489623.5 | |
Uncertain significance (1) |
criteria provided, single submitter
|
Jan 29, 2024 | RCV000795350.5 | |
Uncertain significance (1) |
criteria provided, single submitter
|
Oct 1, 2021 | RCV001788198.1 | |
Benign (1) |
criteria provided, single submitter
|
Nov 22, 2023 | RCV002348069.2 | |
Uncertain significance (1) |
criteria provided, single submitter
|
Aug 31, 2021 | RCV002487428.1 |
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. |
|
---|---|---|---|---|---|
Uncertain significance
(Nov 29, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000577559.4
First in ClinVar: May 22, 2017 Last updated: Apr 17, 2019 |
Comment:
The R40Q variant of uncertain significance in the KCNJ2 gene has been reported as a likely benign variant in one patient with primary electrical disease … (more)
The R40Q variant of uncertain significance in the KCNJ2 gene has been reported as a likely benign variant in one patient with primary electrical disease who also harbors a loss of function variant in the PKP2 gene (Proost et al., 2017). This variant is observed in 6/277196 (0.002%) alleles from individuals of multiple ethnic backgrounds in large population cohorts (Lek et al., 2016). The R40Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. Finally, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign. (less)
|
|
Uncertain significance
(Jan 12, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Atrial fibrillation, familial, 9
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000405990.3
First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020 |
Comment:
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more)
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. (less)
|
|
Uncertain significance
(Jan 12, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Andersen Tawil syndrome
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000405989.3
First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020 |
Comment:
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more)
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. (less)
|
|
Uncertain significance
(Jan 12, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Short QT syndrome type 3
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000405988.3
First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020 |
Comment:
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more)
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. (less)
|
|
Uncertain significance
(Jan 29, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Short QT syndrome type 3
Andersen Tawil syndrome
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV000934806.5
First in ClinVar: Aug 14, 2019 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 40 of the KCNJ2 protein (p.Arg40Gln). … (more)
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 40 of the KCNJ2 protein (p.Arg40Gln). This variant is present in population databases (rs766143485, gnomAD 0.008%). This missense change has been observed in individual(s) with primary electrical disease (PED), however this individual also had a pathogenic variant in another PED-related gene (PMID: 28341588, 29874177). ClinVar contains an entry for this variant (Variation ID: 324830). 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 not expected to disrupt KCNJ2 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects KCNJ2 function (PMID: 29874177). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
|
|
Uncertain significance
(Oct 01, 2021)
|
criteria provided, single submitter
Method: research
|
SUDDEN INFANT DEATH SYNDROME
Affected status: yes
Allele origin:
germline
|
Robert's Program, Boston Children's Hospital
Accession: SCV002030082.1
First in ClinVar: Dec 12, 2021 Last updated: Dec 12, 2021 |
Comment:
We classify this variant as a variant of uncertain significance using ACMG/AMP criteria. As this variant has functional evidence supporting pathogenicty, we suspect this variant … (more)
We classify this variant as a variant of uncertain significance using ACMG/AMP criteria. As this variant has functional evidence supporting pathogenicty, we suspect this variant is favoring pathogenic. (less)
Clinical Features:
Sudden infant death syndrome (present)
Sex: female
|
|
Uncertain significance
(Aug 31, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Andersen Tawil syndrome
Short QT syndrome type 3 Atrial fibrillation, familial, 9
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002787969.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
Uncertain significance
(Mar 08, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV003799755.2
First in ClinVar: Feb 13, 2023 Last updated: Mar 04, 2023 |
Comment:
The KCNJ2 c.119G>A; p.Arg40Gln variant (rs766143485) is reported in the literature in an individual affected with fetal thrombotic vasculopathy (Munroe 2018), and an individual affected … (more)
The KCNJ2 c.119G>A; p.Arg40Gln variant (rs766143485) is reported in the literature in an individual affected with fetal thrombotic vasculopathy (Munroe 2018), and an individual affected with primary electrical disease who also carried a pathogenic PKP2 variant (Proost 2017). This variant is also reported in ClinVar (Variation ID: 324830), but is only observed on five alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The arginine at codon 40 is moderately conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.201). In vitro functional analyses demonstrate reduced channel function (Munroe 2018). However, given the limited clinical and functional data, the significance of this variant is uncertain at this time. References: Munroe PB et al. Postmortem Genetic Testing for Cardiac Ion Channelopathies in Stillbirths. Circ Genom Precis Med. 2018 Jan;11(1):e001817. PMID: 29874177. Proost D et al. Targeted Next-Generation Sequencing of 51 Genes Involved in Primary Electrical Disease. J Mol Diagn. 2017 May;19(3):445-459. PMID: 28341588. (less)
|
|
Benign
(Nov 22, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002646855.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation … (more)
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
|
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 |
---|---|---|---|---|
Postmortem Genetic Testing for Cardiac Ion Channelopathies in Stillbirths. | Munroe PB | Circulation. Genomic and precision medicine | 2018 | PMID: 29874177 |
Targeted Next-Generation Sequencing of 51 Genes Involved in Primary Electrical Disease. | Proost D | The Journal of molecular diagnostics : JMD | 2017 | PMID: 28341588 |
Text-mined citations for rs766143485 ...
HelpRecord last updated May 01, 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.