ClinVar Genomic variation as it relates to human health
NM_016203.4(PRKAG2):c.905G>C (p.Arg302Pro)
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
-
NM_016203.4(PRKAG2):c.905G>C (p.Arg302Pro)
Variation ID: 533881 Accession: VCV000533881.9
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 7q36.1 7: 151576412 (GRCh38) [ NCBI UCSC ] 7: 151273498 (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 May 28, 2018 Feb 14, 2024 Dec 19, 2023 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_016203.4:c.905G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_057287.2:p.Arg302Pro missense NM_001040633.2:c.773G>C NP_001035723.1:p.Arg258Pro missense NM_001304527.2:c.530G>C NP_001291456.1:p.Arg177Pro missense NM_001304531.2:c.182G>C NP_001291460.1:p.Arg61Pro missense NM_001363698.2:c.533G>C NP_001350627.1:p.Arg178Pro missense NM_024429.2:c.182G>C NP_077747.1:p.Arg61Pro missense NC_000007.14:g.151576412C>G NC_000007.13:g.151273498C>G NG_007486.2:g.305820G>C LRG_430:g.305820G>C LRG_430t1:c.905G>C LRG_430p1:p.Arg302Pro - Protein change
- R302P, R177P, R258P, R61P, R178P
- Other names
- -
- Canonical SPDI
- NC_000007.14:151576411:C:G
-
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.
-
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. |
|||
PRKAG2 | No evidence available | No evidence available |
GRCh38 GRCh37 |
1034 | 1213 |
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. |
---|---|---|---|---|
Pathogenic (1) |
criteria provided, single submitter
|
Dec 19, 2023 | RCV000641187.8 | |
Likely pathogenic (1) |
criteria provided, single submitter
|
Feb 23, 2022 | RCV002369682.1 |
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. |
|
---|---|---|---|---|---|
Likely pathogenic
(Feb 23, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002688509.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
The p.R302P variant (also known as c.905G>C), located in coding exon 7 of the PRKAG2 gene, results from a G to C substitution at nucleotide … (more)
The p.R302P variant (also known as c.905G>C), located in coding exon 7 of the PRKAG2 gene, results from a G to C substitution at nucleotide position 905. The arginine at codon 302 is replaced by proline, an amino acid with dissimilar properties. This variant has been detected in several individuals with presentations consistent with PRKAG2-related disease, including hypertrophic cardiomyopathy (HCM) and arrhythmia (Seidelmann SB et al. Circ Cardiovasc Genet, 2017 Feb;10; Hu D et al. EBioMedicine, 2020 Apr;54:102723; Ambry internal data). Another alteration at the same codon, p.R302Q (c.905G>A), has been shown to impact protein function in both in vitro and in vivo functional studies (Scott et al. J Clin Invest. 2004 Jan;113:274-84; Sidhu et al. Circulation. 2005 Jan;111:21-9; Folmes et al. Circ Cardiovasc Genet. 2009 Oct;2:457-66; Zhang et al. J Cardiol. 2013 Oct;62:241-8; Thorn et al. EJNMMI Res. 2013;3:48), and has been seen to segregate with disease in multiple unrelated families described to have Wolff-Parkinson-White syndrome, cardiac conduction system disease, and HCM, or some combination of those presentations (Gollob et al. N Engl J Med. 2001 Jun;344(24):1823-31; Arad et al. J Clin Invest. 2002 Feb;109(3):357-62; Sternick et al. J Cardiovasc Electrophysiol. 2006 Jul; 17(7):724-32; Charron et al. Europace. 2007 Aug;9:597-600; Tan et al. Circ Arrhythm Electrophysiol. 2008 Oct;1:276-81; Thevenon J et al. Europace, 2017 Apr;19:651-659). The p.R302P (c.905G>C) variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
Number of individuals with the variant: 1
|
|
Pathogenic
(Dec 19, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Lethal congenital glycogen storage disease of heart
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV000762825.6
First in ClinVar: May 28, 2018 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 302 of the PRKAG2 protein (p.Arg302Pro). … (more)
This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 302 of the PRKAG2 protein (p.Arg302Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of PRKAG2-related conditions (PMID: 32259713; Invitae). ClinVar contains an entry for this variant (Variation ID: 533881). 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 with a positive predictive value of 95%. This variant disrupts the p.Arg302 amino acid residue in PRKAG2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 14722619, 15611370, 16836667, 20031621, 23992123, 25997934). 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)
|
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 |
---|---|---|---|---|
Identification, clinical manifestation and structural mechanisms of mutations in AMPK associated cardiac glycogen storage disease. | Hu D | EBioMedicine | 2020 | PMID: 32259713 |
Application of Whole Exome Sequencing in the Clinical Diagnosis and Management of Inherited Cardiovascular Diseases in Adults. | Seidelmann SB | Circulation. Cardiovascular genetics | 2017 | PMID: 28087566 |
Using exome sequencing to identify the cause of myocardial hypertrophy in a Chinese family. | Pu T | Molecular medicine reports | 2015 | PMID: 25997934 |
Overexpression of G100S mutation in PRKAG2 causes Wolff-Parkinson-White syndrome in zebrafish. | Zhang BL | Clinical genetics | 2014 | PMID: 23992123 |
Distinct early signaling events resulting from the expression of the PRKAG2 R302Q mutant of AMPK contribute to increased myocardial glycogen. | Folmes KD | Circulation. Cardiovascular genetics | 2009 | PMID: 20031621 |
Familial pseudo-Wolff-Parkinson-White syndrome. | Sternick EB | Journal of cardiovascular electrophysiology | 2006 | PMID: 16836667 |
Transgenic mouse model of ventricular preexcitation and atrioventricular reentrant tachycardia induced by an AMP-activated protein kinase loss-of-function mutation responsible for Wolff-Parkinson-White syndrome. | Sidhu JS | Circulation | 2005 | PMID: 15611370 |
CBS domains form energy-sensing modules whose binding of adenosine ligands is disrupted by disease mutations. | Scott JW | The Journal of clinical investigation | 2004 | PMID: 14722619 |
Text-mined citations for rs121908987 ...
HelpRecord last updated Feb 20, 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.