ClinVar Genomic variation as it relates to human health
NM_016203.4(PRKAG2):c.425C>T (p.Thr142Ile)
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(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_016203.4(PRKAG2):c.425C>T (p.Thr142Ile)
Variation ID: 45717 Accession: VCV000045717.26
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7q36.1 7: 151781193 (GRCh38) [ NCBI UCSC ] 7: 151478279 (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 24, 2016 Feb 14, 2024 Jan 21, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_016203.4:c.425C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_057287.2:p.Thr142Ile missense NM_001040633.2:c.293C>T NP_001035723.1:p.Thr98Ile missense NC_000007.14:g.151781193G>A NC_000007.13:g.151478279G>A NG_007486.2:g.101039C>T LRG_430:g.101039C>T LRG_430t1:c.425C>T LRG_430p1:p.Thr142Ile - Protein change
- T142I, T98I
- Other names
- p.T142I:ACC>ATC
- Canonical SPDI
- NC_000007.14:151781192: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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Allele frequency
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The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00007
The Genome Aggregation Database (gnomAD), exomes 0.00007
Trans-Omics for Precision Medicine (TOPMed) 0.00008
The Genome Aggregation Database (gnomAD) 0.00010
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
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. |
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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
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
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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. |
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Uncertain significance (1) |
criteria provided, single submitter
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Aug 26, 2010 | RCV000038939.7 | |
Likely benign (1) |
criteria provided, single submitter
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Jan 21, 2024 | RCV000226771.10 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jan 12, 2018 | RCV000284645.5 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jan 12, 2018 | RCV000379140.5 | |
Uncertain significance (1) |
no assertion criteria provided
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Jan 26, 2016 | RCV000415017.2 | |
Uncertain significance (1) |
criteria provided, single submitter
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Oct 13, 2021 | RCV000515233.3 | |
Uncertain significance (1) |
no assertion criteria provided
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May 1, 2016 | RCV000491968.2 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Apr 16, 2018 | RCV000656954.2 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Nov 14, 2023 | RCV000769254.8 |
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. |
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Uncertain significance
(Apr 16, 2018)
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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: SCV000208969.13
First in ClinVar: Feb 24, 2015 Last updated: Jul 09, 2018 |
Comment:
The T142I variant has been reported previously in association with dilated cardiomyopathy (DCM) and left ventricular non-compaction (LVNC) (Pugh et al., 2014; Miszalski-Jamka et al., … (more)
The T142I variant has been reported previously in association with dilated cardiomyopathy (DCM) and left ventricular non-compaction (LVNC) (Pugh et al., 2014; Miszalski-Jamka et al., 2017; Walsh et al.., 2017). Pugh et al. (2014) reported T142I as a variant of uncertain significance in one patient who was diagnosed with sporadic DCM. Subsequently, T142I was reported in a patient with LVNC who underwent whole exome sequencing (WES) who also harbored a variant in the ABCC6 gene (Miszalski-Jamka et al., 2017). In addition, the T142I variant has been classified as a variant of uncertain significance by several other clinical laboratories in ClinVar (SCV000062617.5; SCV000290210.2; SCV000290210.2; Landrum et al., 2016). The T142I variant is a non-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Lastly, the T142I variant was observed in 0.0197% (2/10152) of alleles from individuals of Ashkenazi Jewish ancestry in large population cohorts (Lek et al., 2016). (less)
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Uncertain significance
(Dec 28, 2017)
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criteria provided, single submitter
Method: clinical testing
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Not provided
Affected status: unknown
Allele origin:
germline
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Blueprint Genetics
Accession: SCV000927505.1
First in ClinVar: Jul 24, 2019 Last updated: Jul 24, 2019 |
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Uncertain significance
(Aug 26, 2010)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000062617.6
First in ClinVar: May 03, 2013 Last updated: Jul 06, 2018 |
Comment:
The Thr142Ile variant has not been reported in the literature. However, this var iant has been identified by our laboratory in one individual with a … (more)
The Thr142Ile variant has not been reported in the literature. However, this var iant has been identified by our laboratory in one individual with a second, like ly pathogenic mutation and in another individual with a clinical diagnosis of d ilated cardiomyopathy (DCM); PRKAG2 variants are more commonly associated with HCM/LVH and WPW (Oliveira, 2003). In addition, the Thr80Asn variant is located outside the CBS domain region where all pathogenic PRKAG2 variants have been id entified to date. In summary, while these observations suggest that this could be a benign variant, its clinical significance cannot be determined with certain ty at this time. (less)
Number of individuals with the variant: 3
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Uncertain significance
(Jan 12, 2018)
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criteria provided, single submitter
Method: clinical testing
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Wolff-Parkinson-White pattern
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000467645.3
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)
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Uncertain significance
(Jan 12, 2018)
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criteria provided, single submitter
Method: clinical testing
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Hypertrophic cardiomyopathy 6
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000467646.3
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)
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Uncertain significance
(Oct 13, 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: SCV000611505.2
First in ClinVar: Nov 11, 2017 Last updated: Dec 31, 2022 |
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Uncertain significance
(Apr 04, 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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CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Study: Canadian Open Genetics Repository
Accession: SCV000900630.3 First in ClinVar: May 06, 2019 Last updated: Feb 04, 2024 |
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Likely benign
(Jan 21, 2024)
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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: SCV000290210.8
First in ClinVar: Jul 02, 2016 Last updated: Feb 14, 2024 |
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Uncertain significance
(Nov 14, 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: SCV001350803.3
First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces threonine with isoleucine at codon 142 of the PRKAG2 protein. Computational prediction is inconclusive regarding the impact of this variant on … (more)
This missense variant replaces threonine with isoleucine at codon 142 of the PRKAG2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 27532257, 30847666), left ventricular noncompaction (PMID: 28798025), possible arrhythmogenic right ventricular cardiomyopathy (PMID: 29253866), or long QT syndrome (PMID: 33876311). This variant has also been reported in individuals affected with dilated cardiomyopathy (PMID: 24503780, 27532257, 35588295), including one de novo report (PMID: 35588295). This variant has also been identified in 20/282698 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 01, 2016)
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no assertion criteria provided
Method: clinical testing
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Arrhythmogenic right ventricular dysplasia 9
Affected status: yes
Allele origin:
germline
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Institut für Laboratoriums- und Transfusionsmedizin, Herz- und Diabeteszentrum Nordrhein-Westfalen
Accession: SCV000298152.1
First in ClinVar: Jun 25, 2017 Last updated: Jun 25, 2017 |
Number of individuals with the variant: 1
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Uncertain significance
(Jan 26, 2016)
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no assertion criteria provided
Method: clinical testing
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Hypertrophic cardiomyopathy
Affected status: yes
Allele origin:
unknown
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Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV000492664.1
First in ClinVar: Jan 13, 2017 Last updated: Jan 13, 2017 |
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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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Controversial molecular functions of CBS versus non-CBS domain variants of PRKAG2 in arrhythmia and cardiomyopathy: A case report and literature review. | Gong X | Molecular genetics & genomic medicine | 2022 | PMID: 35588295 |
Functional testing for variant prioritization in a family with long QT syndrome. | Najari Beidokhti M | Molecular genetics and genomics : MGG | 2021 | PMID: 33876311 |
Large next-generation sequencing gene panels in genetic heart disease: yield of pathogenic variants and variants of unknown significance. | van Lint FHM | Netherlands heart journal : monthly journal of the Netherlands Society of Cardiology and the Netherlands Heart Foundation | 2019 | PMID: 30847666 |
High proportion of genetic cases in patients with advanced cardiomyopathy including a novel homozygous Plakophilin 2-gene mutation. | Klauke B | PloS one | 2017 | PMID: 29253866 |
Novel Genetic Triggers and Genotype-Phenotype Correlations in Patients With Left Ventricular Noncompaction. | Miszalski-Jamka K | Circulation. Cardiovascular genetics | 2017 | PMID: 28798025 |
Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples. | Walsh R | Genetics in medicine : official journal of the American College of Medical Genetics | 2017 | PMID: 27532257 |
The landscape of genetic variation in dilated cardiomyopathy as surveyed by clinical DNA sequencing. | Pugh TJ | Genetics in medicine : official journal of the American College of Medical Genetics | 2014 | PMID: 24503780 |
Mutation analysis of AMP-activated protein kinase subunits in inherited cardiomyopathies: implications for kinase function and disease pathogenesis. | Oliveira SM | Journal of molecular and cellular cardiology | 2003 | PMID: 14519435 |
Text-mined citations for rs397517270 ...
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.