ClinVar Genomic variation as it relates to human health
NM_016203.4(PRKAG2):c.593C>T (p.Pro198Leu)
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.593C>T (p.Pro198Leu)
Variation ID: 241096 Accession: VCV000241096.17
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7q36.1 7: 151675511 (GRCh38) [ NCBI UCSC ] 7: 151372597 (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 Jul 2, 2016 Feb 20, 2024 Sep 29, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_016203.4:c.593C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_057287.2:p.Pro198Leu missense NM_001040633.2:c.461C>T NP_001035723.1:p.Pro154Leu missense NM_001304527.2:c.221C>T NP_001291456.1:p.Pro74Leu missense NM_001363698.2:c.221C>T NP_001350627.1:p.Pro74Leu missense NC_000007.14:g.151675511G>A NC_000007.13:g.151372597G>A NG_007486.2:g.206721C>T LRG_430:g.206721C>T LRG_430t1:c.593C>T LRG_430p1:p.Pro198Leu - Protein change
- P198L, P154L, P74L
- Other names
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- Canonical SPDI
- NC_000007.14:151675510: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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0.00020 (A)
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Allele frequency
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The frequency of the allele represented by this VCV record.
1000 Genomes Project 0.00020
Trans-Omics for Precision Medicine (TOPMed) 0.00004
The Genome Aggregation Database (gnomAD) 0.00005
1000 Genomes Project 30x 0.00016
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 |
1035 | 1209 |
Conditions - Germline
Condition
Help
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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Uncertain significance (1) |
criteria provided, single submitter
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May 5, 2023 | RCV000233598.5 | |
Uncertain significance (2) |
criteria provided, single submitter
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Sep 8, 2017 | RCV000519766.2 | |
Uncertain significance (1) |
criteria provided, single submitter
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Apr 4, 2022 | RCV000619075.2 | |
Uncertain significance (1) |
criteria provided, single submitter
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Sep 29, 2023 | RCV001180377.4 | |
Uncertain significance (1) |
criteria provided, single submitter
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Sep 6, 2021 | RCV002487082.1 | |
not provided (1) |
no classification provided
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- | RCV003483592.1 |
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
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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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Uncertain significance
(Sep 08, 2017)
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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: SCV000620696.2
First in ClinVar: Dec 19, 2017 Last updated: Dec 19, 2017 |
Comment:
The P198L variant of uncertain significance in the PRKAG2 gene has not been published in association with PRKAG2-related disorders to our knowledge. This variant is … (more)
The P198L variant of uncertain significance in the PRKAG2 gene has not been published in association with PRKAG2-related disorders to our knowledge. This variant is also not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Additionally, P198L is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. However, this substitution occurs at a position that is not conserved across species and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Finally, while another missense variant at the same residue (P198A) has been reported in HGMD in association with HCM (Stenson et al., 2014; Alejandra Restrepo-Cordoba et al., 2017), the clinical significance of this variant also remains to be definitively determined. (less)
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Uncertain significance
(Apr 04, 2022)
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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: SCV000736832.4
First in ClinVar: Apr 14, 2018 Last updated: Nov 29, 2022 |
Comment:
The p.P198L variant (also known as c.593C>T), located in coding exon 4 of the PRKAG2 gene, results from a C to T substitution at nucleotide … (more)
The p.P198L variant (also known as c.593C>T), located in coding exon 4 of the PRKAG2 gene, results from a C to T substitution at nucleotide position 593. The proline at codon 198 is replaced by leucine, an amino acid with similar properties. This alteration has been reported in an autism spectrum disorder cohort that had whole exome sequencing (Jiao J et al. J Mol Neurosci, 2020 Feb;70:219-229). This amino acid position is highly 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)
Number of individuals with the variant: 1
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Uncertain significance
(Sep 29, 2023)
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criteria provided, single submitter
Method: clinical testing
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Cardiomyopathy
Affected status: unknown
Allele origin:
germline
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Color Diagnostics, LLC DBA Color Health
Accession: SCV001345297.3
First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces proline with leucine at codon 198 of the PRKAG2 protein. Computational prediction suggests that this variant may not impact protein structure … (more)
This missense variant replaces proline with leucine at codon 198 of the PRKAG2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with PRKAG2-related disorders in the literature. This variant has been identified in 6/282504 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
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Uncertain significance
(May 05, 2023)
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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: SCV000290212.6
First in ClinVar: Jul 02, 2016 Last updated: Feb 20, 2024 |
Comment:
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 … (more)
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. 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 PRKAG2 protein function. ClinVar contains an entry for this variant (Variation ID: 241096). This variant has not been reported in the literature in individuals affected with PRKAG2-related conditions. This variant is present in population databases (rs41317142, gnomAD 0.004%). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 198 of the PRKAG2 protein (p.Pro198Leu). (less)
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Uncertain significance
(Sep 06, 2021)
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criteria provided, single submitter
Method: clinical testing
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Wolff-Parkinson-White pattern
Lethal congenital glycogen storage disease of heart Hypertrophic cardiomyopathy 6
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002794126.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Uncertain significance
(Jun 21, 2016)
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no assertion criteria provided
Method: provider interpretation
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not provided
Affected status: unknown
Allele origin:
germline
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Stanford Center for Inherited Cardiovascular Disease, Stanford University
Accession: SCV000924912.1
First in ClinVar: Jun 29, 2019 Last updated: Jun 29, 2019 |
Comment:
We have seen this variant in an individual with LVNC. Testing was done at Invitae. Given the lack of case data we consider this variant … (more)
We have seen this variant in an individual with LVNC. Testing was done at Invitae. Given the lack of case data we consider this variant to be uncertain significance and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The variant has not been reported in the literature. The Invitae report notes: The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and leucine. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. The P198L variant was reported online in 1 of 60,507 individuals in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of 4/2016). Specifically, the variant was observed in 1 of 5,780 Latino people. A different P198R variant at the same codon was reported online in 7 of 60,507 individuals in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of 4/2016). Specifically, the variant was observed in 5 of 4,323 East Asian people and 2 of 33,224 non-Finnish European people. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. (less)
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not provided
(-)
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no classification provided
Method: phenotyping only
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PRKAG2 cardiac syndrome
Affected status: unknown
Allele origin:
unknown
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GenomeConnect - Invitae Patient Insights Network
Accession: SCV004228810.1
First in ClinVar: Jan 26, 2024 Last updated: Jan 26, 2024 |
Comment:
Variant interpreted as Uncertain significance and reported on 01-04-2021 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the … (more)
Variant interpreted as Uncertain significance and reported on 01-04-2021 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. (less)
Clinical Features:
Phenotypic abnormality (present)
Indication for testing: Diagnostic
Age: 50-59 years
Sex: male
Method: Gene Panel Sequencing
Testing laboratory: Invitae
Date variant was reported to submitter: 2021-01-04
Testing laboratory interpretation: Uncertain significance
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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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Identification of De Novo JAK2 and MAPK7 Mutations Related to Autism Spectrum Disorder Using Whole-Exome Sequencing in a Chinese Child and Adolescent Trio-Based Sample. | Jiao J | Journal of molecular neuroscience : MN | 2020 | PMID: 31838722 |
Text-mined citations for rs41317142 ...
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.