ClinVar Genomic variation as it relates to human health
NM_016203.4(PRKAG2):c.698C>G (p.Ala233Gly)
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); Likely benign(4)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_016203.4(PRKAG2):c.698C>G (p.Ala233Gly)
Variation ID: 45733 Accession: VCV000045733.51
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 7q36.1 7: 151632125 (GRCh38) [ NCBI UCSC ] 7: 151329211 (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 Jan 31, 2015 Mar 10, 2024 Jan 25, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_016203.4:c.698C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_057287.2:p.Ala233Gly missense NM_001040633.2:c.566C>G NP_001035723.1:p.Ala189Gly missense NM_001304527.2:c.326C>G NP_001291456.1:p.Ala109Gly missense NM_001304531.2:c.-26C>G 5 prime UTR NM_001363698.2:c.326C>G NP_001350627.1:p.Ala109Gly missense NM_024429.2:c.-26C>G 5 prime UTR NC_000007.14:g.151632125G>C NC_000007.13:g.151329211G>C NG_007486.2:g.250107C>G LRG_430:g.250107C>G LRG_430t1:c.698C>G LRG_430p1:p.Ala233Gly - Protein change
- A233G, A189G, A109G
- Other names
- -
- Canonical SPDI
- NC_000007.14:151632124:G:C
-
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.
Trans-Omics for Precision Medicine (TOPMed) 0.00014
The Genome Aggregation Database (gnomAD) 0.00015
1000 Genomes Project 30x 0.00016
The Genome Aggregation Database (gnomAD), exomes 0.00017
Exome Aggregation Consortium (ExAC) 0.00022
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 | |
LOC129999660 | - | - | - | GRCh38 | - | 111 |
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
|
Nov 14, 2012 | RCV000038955.7 | |
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
|
May 1, 2023 | RCV000588424.22 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
|
May 16, 2023 | RCV000769246.10 | |
Likely benign (1) |
criteria provided, single submitter
|
Jan 25, 2024 | RCV000699614.10 | |
Uncertain significance (1) |
criteria provided, single submitter
|
Jan 12, 2018 | RCV001161541.5 | |
Uncertain significance (1) |
criteria provided, single submitter
|
Jan 12, 2018 | RCV001161542.5 | |
Uncertain significance (1) |
criteria provided, single submitter
|
Jan 1, 2016 | RCV001199301.3 | |
Uncertain significance (1) |
criteria provided, single submitter
|
Nov 18, 2019 | RCV001256863.3 | |
Uncertain significance (1) |
criteria provided, single submitter
|
Mar 3, 2023 | RCV003162342.2 |
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. |
|
---|---|---|---|---|---|
Likely benign
(Mar 28, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000699420.1
First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018 |
Comment:
Variant summary: The PRKAG2 c.698C>G (p.Ala233Gly) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a benign outcome for this variant. … (more)
Variant summary: The PRKAG2 c.698C>G (p.Ala233Gly) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a benign outcome for this variant. This variant was found in 17/77136 control chromosomes, predominantly observed in the European subpopulation at a frequency of 0.000371 (17/45836). This frequency is about 15 times the estimated maximal expected allele frequency of a pathogenic PRKAG2 variant (0.000025), suggesting this is likely a benign polymorphism found primarily in the populations of European origin. One clinical diagnostic laboratory identified this variant in one infant with unspecified cardiomyopathy and classified this variant as uncertain significance without additional evidence for independent review. One reputable database classified this variant as "unlikely to be pathogenic". Taken together, this variant is classified as likely benign. (less)
|
|
Uncertain significance
(Nov 14, 2012)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: not provided
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000062633.6
First in ClinVar: May 03, 2013 Last updated: Jan 31, 2015 |
Comment:
Variant classified as Uncertain Significance - Favor Benign. The Ala233Gly varia nt in PRKAG2 has not been reported in the literature, but has been identified … (more)
Variant classified as Uncertain Significance - Favor Benign. The Ala233Gly varia nt in PRKAG2 has not been reported in the literature, but has been identified in one infant with unspecified cardiomyopathy previously tested by our laboratory. This variant is located outside of the CBS domain, where all pathogenic PRKAG2 mutations have been identified to date (Oliveira 2003), raising the possibility that it may be tolerated. Computational analyses (biochemical amino acid propert ies, conservation, AlignGVGD, PolyPhen2, and SIFT) also suggest that the Ala233G ly variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, additional information is needed to fully assess the clinical significance of the Ala233Gly variant. (less)
Number of individuals with the variant: 3
|
|
Uncertain significance
(Nov 18, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Hypertrophic cardiomyopathy 1
Affected status: yes
Allele origin:
germline
|
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute
Accession: SCV001433354.1
First in ClinVar: Sep 27, 2020 Last updated: Sep 27, 2020 |
|
|
Uncertain significance
(Oct 20, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000581876.4
First in ClinVar: Jan 31, 2015 Last updated: Dec 24, 2022 |
Comment:
Reported in a patient with hypoplastic left heart and left ventricular noncompaction in published literature (Ritter et al., 2019); In silico analysis supports that this … (more)
Reported in a patient with hypoplastic left heart and left ventricular noncompaction in published literature (Ritter et al., 2019); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31527676) (less)
|
|
Uncertain significance
(Jan 12, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Wolff-Parkinson-White pattern
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV001323428.1
First in ClinVar: May 31, 2020 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
|
Hypertrophic cardiomyopathy 6
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV001323429.1
First in ClinVar: May 31, 2020 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)
|
|
Likely benign
(Nov 12, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiomyopathy
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV000904655.2
First in ClinVar: May 20, 2019 Last updated: Jun 22, 2020 |
|
|
Uncertain significance
(Jan 01, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
see cases
Affected status: yes
Allele origin:
unknown
|
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV001370379.2
First in ClinVar: Jul 04, 2020 Last updated: Jul 04, 2020 |
Comment:
This variant was classified as: Uncertain significance.
Clinical Features:
Prolonged QT interval (present) , Cardiac arrest (present) , Ventricular tachycardia (present) , Ventricular extrasystoles (present) , Arrhythmia (present)
|
|
Uncertain significance
(Mar 03, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV003902557.1
First in ClinVar: Apr 15, 2023 Last updated: Apr 15, 2023 |
Comment:
The p.A233G variant (also known as c.698C>G), located in coding exon 5 of the PRKAG2 gene, results from a C to G substitution at nucleotide … (more)
The p.A233G variant (also known as c.698C>G), located in coding exon 5 of the PRKAG2 gene, results from a C to G substitution at nucleotide position 698. The alanine at codon 233 is replaced by glycine, an amino acid with similar properties. This alteration has been reported in an acute heart failure in infancy cohort; however, clinical details were limited (Ritter A et al. Genet Med, 2020 Feb;22:423-426). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
|
|
Uncertain significance
(May 16, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiomyopathy
Affected status: unknown
Allele origin:
germline
|
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Study: Canadian Open Genetics Repository
Accession: SCV000900622.3 First in ClinVar: May 06, 2019 Last updated: Feb 04, 2024 |
|
|
Likely benign
(Jan 25, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Lethal congenital glycogen storage disease of heart
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV000828333.7
First in ClinVar: Oct 10, 2018 Last updated: Feb 20, 2024 |
|
|
Likely benign
(May 01, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV000892811.21
First in ClinVar: Mar 31, 2019 Last updated: Mar 10, 2024 |
Comment:
PRKAG2: BP4
Number of individuals with the variant: 6
|
|
click to load more click to collapse |
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 |
---|---|---|---|---|
Clinical utility of exome sequencing in infantile heart failure. | Ritter A | Genetics in medicine : official journal of the American College of Medical Genetics | 2020 | PMID: 31527676 |
Text-mined citations for rs201240745 ...
HelpRecord last updated Mar 11, 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.