ClinVar Genomic variation as it relates to human health
NM_016203.4(PRKAG2):c.1589A>G (p.His530Arg)
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_016203.4(PRKAG2):c.1589A>G (p.His530Arg)
Variation ID: 6854 Accession: VCV000006854.9
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7q36.1 7: 151560613 (GRCh38) [ NCBI UCSC ] 7: 151257699 (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 Feb 24, 2015 Feb 20, 2024 Jul 29, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_016203.4:c.1589A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_057287.2:p.His530Arg missense NM_001040633.2:c.1457A>G NP_001035723.1:p.His486Arg missense NM_001304527.2:c.1214A>G NP_001291456.1:p.His405Arg missense NM_001304531.2:c.866A>G NP_001291460.1:p.His289Arg missense NM_001363698.2:c.1217A>G NP_001350627.1:p.His406Arg missense NM_024429.2:c.866A>G NP_077747.1:p.His289Arg missense NC_000007.14:g.151560613T>C NC_000007.13:g.151257699T>C NG_007486.2:g.321619A>G LRG_430:g.321619A>G LRG_430t1:c.1589A>G LRG_430p1:p.His530Arg - Protein change
- H530R, H406R, H289R, H486R, H405R
- Other names
- p.H530R:CAT>CGT
- Canonical SPDI
- NC_000007.14:151560612:T:C
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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
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The frequency of the allele represented by this VCV record.
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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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PRKAG2 | No evidence available | No evidence available |
GRCh38 GRCh37 |
1107 | 1281 |
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
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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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Pathogenic (1) |
no assertion criteria provided
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May 1, 2008 | RCV000007257.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 8, 2012 | RCV000159018.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 29, 2022 | RCV000813711.5 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 7, 2018 | RCV000852579.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 11, 2021 | RCV002399313.1 |
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
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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
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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
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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
(Mar 08, 2012)
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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: SCV000208960.9
First in ClinVar: Feb 24, 2015 Last updated: Feb 24, 2015 |
Comment:
p.His530Arg (CAT>CGT:c.1598 A>G in exon 15 of the PRKAG2 gene (NM_016203.3) The His530Arg mutation in the PRKAG2 gene has been reported previously in one individual … (more)
p.His530Arg (CAT>CGT:c.1598 A>G in exon 15 of the PRKAG2 gene (NM_016203.3) The His530Arg mutation in the PRKAG2 gene has been reported previously in one individual with childhood-onset HCM, and this mutation was absent from >1,000 control alleles. In addition, the NHLBI ESP Exome Variant Server reports His530Arg was not observed in approximately 5,000 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. Although His530Arg results in a conservative substitution of one positively charged amino acid for another, the His530 residue is conserved across species. Mutations in a neighboring codon (Arg531Gln, Arg531Gly) have also been reported in association with PRKAG2-related phenotypes, supporting the functional importance of this region of the protein. In summary, the presence of His530Arg in the PRKAG2 gene is consistent with a diagnosis of a PRKAG2-related cardiomyopathy and/or Wolff-Parkinson-White (WPW) syndrome. The variant is found in HCM panel(s). (less)
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Pathogenic
(Feb 07, 2018)
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criteria provided, single submitter
Method: clinical testing
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Hypertrophic cardiomyopathy
Affected status: yes
Allele origin:
germline
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Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego
Accession: SCV000995280.1
First in ClinVar: Oct 12, 2019 Last updated: Oct 12, 2019 |
Number of individuals with the variant: 1
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Pathogenic
(Oct 11, 2021)
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criteria provided, single submitter
Method: clinical testing
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Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV002705691.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
The p.H530R pathogenic mutation (also known as c.1589A>G), located in coding exon 15 of the PRKAG2 gene, results from an A to G substitution at … (more)
The p.H530R pathogenic mutation (also known as c.1589A>G), located in coding exon 15 of the PRKAG2 gene, results from an A to G substitution at nucleotide position 1589. The histidine at codon 530 is replaced by arginine, an amino acid with highly similar properties. This variant has been reported in individuals with hypertrophic cardiomyopathy (HCM), Wolff-Parkinson-White syndrome, and other cardiac arrhythmias, and it has been shown to segregate with disease in affected family members (Morita H et al. N Engl J Med, 2008 May;358:1899-908; Epicoco G et al. JACC Clin Electrophysiol, 2018 10;4:1377-1378; Aggarwal V et al. Ann Pediatr Cardiol;8:153-6; Xie C et al. Cell Res, 2016 Oct;26:1099-1111; Thevenon J et al. Europace, 2017 Apr;19:651-659; Lu C et al. J Transl Med, 2018 08;16:241). Functional studies in transgenic mouse models demonstrated consistent PRKAG2-related cardiac findings, including significant glycogen accumulation (Xie C et al. Cell Res, 2016 Oct;26:1099-1111). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
Number of individuals with the variant: 1
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Pathogenic
(Jul 29, 2022)
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criteria provided, single submitter
Method: clinical testing
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Lethal congenital glycogen storage disease of heart
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000954081.3
First in ClinVar: Aug 14, 2019 Last updated: Feb 20, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this … (more)
For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Experimental studies have shown that this missense change affects PRKAG2 function (PMID: 27573176). 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 PRKAG2 protein function. ClinVar contains an entry for this variant (Variation ID: 6854). This missense change has been observed in individuals with PRKAG2-related cardiac conditions, including hypertrophic cardiomyopathy and Wolff-Parkinson-White syndrome (PMID: 18403758, 26085771, 27189955; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 530 of the PRKAG2 protein (p.His530Arg). (less)
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Pathogenic
(May 01, 2008)
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no assertion criteria provided
Method: literature only
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CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 6
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000027453.3
First in ClinVar: Apr 04, 2013 Last updated: Oct 20, 2016 |
Comment on evidence:
In a child with idiopathic cardiac hypertrophy and presumed sporadic cardiomyopathy (CMH6; 600858), who was negative for mutations in 9 of the known CMH genes, … (more)
In a child with idiopathic cardiac hypertrophy and presumed sporadic cardiomyopathy (CMH6; 600858), who was negative for mutations in 9 of the known CMH genes, Morita et al. (2008) identified heterozygosity for an A-to-G transition in the PRKAG2 gene, resulting in a his530-to-arg (H530R) substitution. (The parents were not studied.) The mutation was not found in unrelated individuals matched by ancestral origin or in more than 1,000 control chromosomes. (less)
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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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Cardiac MR manifestations in two cases of PRKAG2 mutations in a Chinese family. | Wang J | The international journal of cardiovascular imaging | 2020 | PMID: 32314121 |
An Unusual Pattern of Ventricular Pre-Excitation: Electrophysiological and Genetic Substrate. | Epicoco G | JACC. Clinical electrophysiology | 2018 | PMID: 30336887 |
Molecular analysis of inherited cardiomyopathy using next generation semiconductor sequencing technologies. | Lu C | Journal of translational medicine | 2018 | PMID: 30165862 |
High prevalence of arrhythmic and myocardial complications in patients with cardiac glycogenosis due to PRKAG2 mutations. | Thevenon J | Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology | 2017 | PMID: 28431061 |
Genome editing with CRISPR/Cas9 in postnatal mice corrects PRKAG2 cardiac syndrome. | Xie C | Cell research | 2016 | PMID: 27573176 |
PRKAG2 mutation: An easily missed cardiac specific non-lysosomal glycogenosis. | Aggarwal V | Annals of pediatric cardiology | 2015 | PMID: 26085771 |
Shared genetic causes of cardiac hypertrophy in children and adults. | Morita H | The New England journal of medicine | 2008 | PMID: 18403758 |
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Text-mined citations for rs267606977 ...
HelpRecord last updated Feb 28, 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.