rs267606977

chr7-151560613-T-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_016203.4(PRKAG2):c.1589A>G(p.His530Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H530D) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PRKAG2 NM_016203.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 7.81

Genes affected

PRKAG2 (HGNC:9386): (protein kinase AMP-activated non-catalytic subunit gamma 2) AMP-activated protein kinase (AMPK) is a heterotrimeric protein composed of a catalytic alpha subunit, a noncatalytic beta subunit, and a noncatalytic regulatory gamma subunit. Various forms of each of these subunits exist, encoded by different genes. AMPK is an important energy-sensing enzyme that monitors cellular energy status and functions by inactivating key enzymes involved in regulating de novo biosynthesis of fatty acid and cholesterol. This gene is a member of the AMPK gamma subunit family. Mutations in this gene have been associated with Wolff-Parkinson-White syndrome, familial hypertrophic cardiomyopathy, and glycogen storage disease of the heart. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. [provided by RefSeq, Jan 2015]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a binding_site (size 1) in uniprot entity AAKG2_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_016203.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-151560614-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 855977.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.968
• PP5: Variant 7-151560613-T-C is Pathogenic according to our data. Variant chr7-151560613-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 6854.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRKAG2	NM_016203.4	c.1589A>G	p.His530Arg	missense_variant	15/16	ENST00000287878.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRKAG2	ENST00000287878.9	c.1589A>G	p.His530Arg	missense_variant	15/16	1	NM_016203.4	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 08, 2012

p.His530Arg (CAT>CGT:c.1598 A>G in exon 15 of the PRKAG2 gene (NM_016203.3) The His530Arg mutation in the PRKAG2 gene has been reported previously in one individual with childhood-onset HCM, and this mutation was absent from >1,000 control alleles. In addition, the NHLBI ESP Exome Variant Server reports His530Arg was not observed in approximately 5,000 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. Although His530Arg results in a conservative substitution of one positively charged amino acid for another, the His530 residue is conserved across species. Mutations in a neighboring codon (Arg531Gln, Arg531Gly) have also been reported in association with PRKAG2-related phenotypes, supporting the functional importance of this region of the protein. In summary, the presence of His530Arg in the PRKAG2 gene is consistent with a diagnosis of a PRKAG2-related cardiomyopathy and/or Wolff-Parkinson-White (WPW) syndrome. The variant is found in HCM panel(s). -

Hypertrophic cardiomyopathy 6 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 01, 2008

- -

Hypertrophic cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

Feb 07, 2018

- -

Lethal congenital glycogen storage disease of heart Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jul 29, 2022

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Experimental studies have shown that this missense change affects PRKAG2 function (PMID: 27573176). 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. ClinVar contains an entry for this variant (Variation ID: 6854). This missense change has been observed in individuals with PRKAG2-related cardiac conditions, including hypertrophic cardiomyopathy and Wolff-Parkinson-White syndrome (PMID: 18403758, 26085771, 27189955; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 530 of the PRKAG2 protein (p.His530Arg). -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 11, 2021

The p.H530R pathogenic mutation (also known as c.1589A>G), located in coding exon 15 of the PRKAG2 gene, results from an A to G substitution at nucleotide position 1589. The histidine at codon 530 is replaced by arginine, an amino acid with highly similar properties. This variant has been reported in individuals with hypertrophic cardiomyopathy (HCM), Wolff-Parkinson-White syndrome, and other cardiac arrhythmias, and it has been shown to segregate with disease in affected family members (Morita H et al. N Engl J Med, 2008 May;358:1899-908; Epicoco G et al. JACC Clin Electrophysiol, 2018 10;4:1377-1378; Aggarwal V et al. Ann Pediatr Cardiol;8:153-6; Xie C et al. Cell Res, 2016 Oct;26:1099-1111; Thevenon J et al. Europace, 2017 Apr;19:651-659; Lu C et al. J Transl Med, 2018 08;16:241). Functional studies in transgenic mouse models demonstrated consistent PRKAG2-related cardiac findings, including significant glycogen accumulation (Xie C et al. Cell Res, 2016 Oct;26:1099-1111). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
CardioboostCm	Uncertain	0.88
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.80	D;.;.;.
Eigen	Uncertain	0.68
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.97	D;D;D;D
MetaSVM	Uncertain	0.75	D
MutationAssessor	Uncertain	2.8	M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-7.4	D;D;D;D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.013	D;D;D;D
Sift4G	Pathogenic	0.0	D;T;D;D
Polyphen		0.89	P;.;.;.
Vest4		0.97
MutPred		0.88		Gain of MoRF binding (P = 0.0425);.;.;.;
MVP		0.98
MPC		1.8
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.84
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs267606977; hg19: chr7-151257699;