VCV000045688.78 - ClinVar

NM_016203.4(PRKAG2):c.111T>A (p.Ile37=)

Germline

Classification

criteria provided, conflicting classifications. Learn more about how ClinVar calculates review status.

Conflicting classifications of pathogenicity
Uncertain significance (1); Benign (10); Likely benign (3)

14 out of 20 submissions contributed to this classification

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.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_016203.4(PRKAG2):c.111T>A (p.Ile37=)

Variation ID: 45688 Accession: VCV000045688.78

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 7q36.1 7: 151876510 (GRCh38) [ NCBI UCSC ] 7: 151573595 (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	Jun 28, 2015	Jun 20, 2026	Jan 31, 2026

HGVS

Nucleotide	Protein	Molecular consequence
NM_016203.4:c.111T>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_057287.2:p.Ile37=	synonymous
NC_000007.14:g.151876510A>T
NC_000007.13:g.151573595A>T
NG_007486.1:g.5722T>A
LRG_430t1:c.111T>A	LRG_430p1:p.Ile37=

... more HGVS ... less HGVS

Protein change

Other names

p.Ile37=

Canonical SPDI

NC_000007.14:151876509:A:T

Global minor allele frequency (GMAF) Help The 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.

0.00100 (T)

Allele frequency Help The frequency of the allele represented by this VCV record.

1000 Genomes Project 30x 0.00094

1000 Genomes Project 0.00100

Exome Aggregation Consortium (ExAC) 0.00197

The Genome Aggregation Database (gnomAD), exomes 0.00242

The Genome Aggregation Database (gnomAD) 0.00247

The Genome Aggregation Database (gnomAD) 0.00259

Trans-Omics for Precision Medicine (TOPMed) 0.00287

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00392

The Genome Aggregation Database (gnomAD), exomes 0.00429

Links

ClinGen: CA013584 dbSNP: rs144426409 VarSome

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
Gene	OMIM	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	1398	1600

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.
not specified	Benign (9)	criteria provided, multiple submitters, no conflicts	Apr 9, 2025	RCV000038906.25
Lethal congenital glycogen storage disease of heart	Benign (1)	criteria provided, single submitter	Jan 31, 2026	RCV000228988.25
Cardiovascular phenotype	Likely benign (1)	criteria provided, single submitter	Jul 28, 2016	RCV000244616.12
Wolff-Parkinson-White pattern	Likely benign (1)	criteria provided, single submitter	Jan 12, 2018	RCV000277990.13
Hypertrophic cardiomyopathy 6	Uncertain significance (1)	criteria provided, single submitter	Jan 12, 2018	RCV000372444.13
Cardiomyopathy	Benign (2)	criteria provided, multiple submitters, no conflicts	Mar 14, 2018	RCV000770266.12
not provided	Benign/Likely benign (4)	criteria provided, multiple submitters, no conflicts	Jun 13, 2025	RCV001529843.49
Hypertrophic cardiomyopathy	Benign (1)	no assertion criteria provided	Sep 29, 2022	RCV003125867.9

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.	Expand all rows Collapse all rows 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.
Benign (Oct 30, 2017) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Cardiomyopathy	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario Study: Canadian Open Genetics Repository Accession: SCV000901698.1 First in ClinVar: May 06, 2019 Last updated: May 06, 2019	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Benign (May 29, 2018) C Contributing to aggregate classification	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	not specified	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000918092.1 First in ClinVar: Jun 02, 2019 Last updated: Jun 02, 2019	Comment: show Variant summary: PRKAG2 c.111T>A alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0023 in 271072 control chromosomes in the gnomAD database, including 1 homozygotes. The observed variant frequency is approximately 94-folds higher than the estimated maximal expected allele frequency for a pathogenic variant in PRKAG2 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.111T>A in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Multiple ClinVar submissions from clinical diagnostic laboratories cite the variant predominantly as "likely benign/benign" (2x) and once as "uncertain significance." Based on the evidence outlined above, the variant was classified as benign. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Benign (Mar 01, 2012) C Contributing to aggregate classification	criteria provided, single submitter (LMM Criteria)	not specified	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000062584.6 First in ClinVar: May 03, 2013 Last updated: Jun 02, 2019	Comment: show Ile37Ile in exon 1 of PRKAG2: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue and has been identified in 0.5% (33/7020) of European American chromosomes from a broad population by t he NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs144 426409). (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: not provided more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: not provided Number of individuals with the variant: 33

Uncertain significance (Jan 12, 2018) C Contributing to aggregate classification	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Hypertrophic cardiomyopathy 6	Illumina Laboratory Services, Illumina Accession: SCV000467682.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: show 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) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Likely benign (Jan 12, 2018) C Contributing to aggregate classification	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Wolff-Parkinson-White pattern	Illumina Laboratory Services, Illumina Accession: SCV000467683.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: show 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Likely benign (Jul 28, 2016) C Contributing to aggregate classification	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Cardiovascular phenotype	Ambry Genetics Accession: SCV000318062.7 First in ClinVar: Oct 02, 2016 Last updated: May 01, 2024	Comment: show This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Benign (Jun 13, 2025) C Contributing to aggregate classification	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024)	not provided	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV002049109.3 First in ClinVar: Jan 08, 2022 Last updated: Jan 24, 2026	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Benign (Mar 14, 2018) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Cardiomyopathy	Color Diagnostics, LLC DBA Color Health Accession: SCV000910836.1 First in ClinVar: May 20, 2019 Last updated: May 20, 2019	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Platform type: NGS

Benign (Jun 21, 2024) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Not specified	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV007304241.1 First in ClinVar: Jan 17, 2026 Last updated: Jan 17, 2026	Comment: show BS1, BP4, BP7 (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Number of individuals with the variant: 26

Benign (Mar 03, 2015) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	not provided	GeneDx Accession: SCV001891885.1 First in ClinVar: Sep 19, 2021 Last updated: Sep 19, 2021	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Benign (Nov 21, 2014) C Contributing to aggregate classification	criteria provided, single submitter (EGL Classification Definitions 2015)	not specified	Eurofins Ntd Llc (ga) Accession: SCV000224570.6 First in ClinVar: Jun 28, 2015 Last updated: Apr 13, 2025	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=PRKAG2 Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Number of individuals with the variant: 1 Zygosity: 1 Single Heterozygote Sex: mixed

Benign (Apr 09, 2025) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	not specified	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute Accession: SCV006067865.1 First in ClinVar: May 03, 2025 Last updated: May 03, 2025	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: no Observation 1 Collection method: clinical testing Allele origin: germline Affected status: no

Benign (Jan 31, 2026) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Lethal congenital glycogen storage disease of heart	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000290199.12 First in ClinVar: Jul 02, 2016 Last updated: Feb 15, 2026	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Likely benign (Jun 01, 2025) C Contributing to aggregate classification	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	not provided	CeGaT Center for Human Genetics Tuebingen Accession: SCV001746939.32 First in ClinVar: Jul 10, 2021 Last updated: Jun 20, 2026	Comment: show PRKAG2: BP4, BP7, BS2 (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes Number of individuals with the variant: 17

Benign (-) N Not contributing to aggregate classification	no assertion criteria provided	not specified	Genome Diagnostics Laboratory, University Medical Center Utrecht Study: VKGL Data-share Consensus Accession: SCV001927781.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Benign (Sep 29, 2022) N Not contributing to aggregate classification	no assertion criteria provided (ACMG Guidelines, 2015)	Hypertrophic Cardiomyopathy	Cohesion Phenomics Accession: SCV003803054.1 First in ClinVar: Feb 18, 2023 Last updated: Feb 18, 2023	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Likely benign (-) N Not contributing to aggregate classification	no assertion criteria provided	not provided	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001744020.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Benign (-) N Not contributing to aggregate classification	no assertion criteria provided	not specified	Clinical Genetics, Academic Medical Center Study: VKGL Data-share Consensus Accession: SCV001925945.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Benign (-) N Not contributing to aggregate classification	no assertion criteria provided	not specified	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Study: VKGL Data-share Consensus Accession: SCV001955860.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Benign (-) N Not contributing to aggregate classification	no assertion criteria provided	not specified	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Study: VKGL Data-share Consensus Accession: SCV001968379.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Comment:

Variant summary: PRKAG2 c.111T>A alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0023 in 271072 control chromosomes in the gnomAD database, including 1 homozygotes. The observed variant frequency is approximately 94-folds higher than the estimated maximal expected allele frequency for a pathogenic variant in PRKAG2 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.111T>A in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Multiple ClinVar submissions from clinical diagnostic laboratories cite the variant predominantly as "likely benign/benign" (2x) and once as "uncertain significance." Based on the evidence outlined above, the variant was classified as benign.

Comment:

Ile37Ile in exon 1 of PRKAG2: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue and has been identified in 0.5% (33/7020) of European American chromosomes from a broad population by t he NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs144 426409).

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 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.

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 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.

Comment:

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=PRKAG2	-	-	-	-

Text-mined citations for rs144426409 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Jun 20, 2026