7-151576412-C-G

Position:

• chr7-151576412-C-G

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_016203.4(PRKAG2):​c.905G>C​(p.Arg302Pro) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R302Q) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: PRKAG2 NM_016203.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.70

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]

PRKAG2 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a binding_site (size 0) in uniprot entity AAKG2_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-151576412-C-T is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.915
• PP5: Variant 7-151576412-C-G is Pathogenic according to our data. Variant chr7-151576412-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 533881.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRKAG2	NM_016203.4	c.905G>C	p.Arg302Pro	missense_variant	7/16	ENST00000287878.9	NP_057287.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRKAG2	ENST00000287878.9	c.905G>C	p.Arg302Pro	missense_variant	7/16	1	NM_016203.4	ENSP00000287878.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Lethal congenital glycogen storage disease of heart Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 19, 2023

This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 302 of the PRKAG2 protein (p.Arg302Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of PRKAG2-related conditions (PMID: 32259713; Invitae). ClinVar contains an entry for this variant (Variation ID: 533881). 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 with a positive predictive value of 95%. This variant disrupts the p.Arg302 amino acid residue in PRKAG2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 14722619, 15611370, 16836667, 20031621, 23992123, 25997934). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 30, 2024

The p.R302P variant (also known as c.905G>C), located in coding exon 7 of the PRKAG2 gene, results from a G to C substitution at nucleotide position 905. The arginine at codon 302 is replaced by proline, an amino acid with dissimilar properties. This variant has been detected in several individuals with presentations consistent with PRKAG2-related disease, including hypertrophic cardiomyopathy (HCM) and arrhythmia (Seidelmann SB et al. Circ Cardiovasc Genet, 2017 Feb;10; Hu D et al. EBioMedicine, 2020 Apr;54:102723; Ambry internal data). Another alteration at the same codon, p.R302Q (c.905G>A), has been shown to impact protein function in both in vitro and in vivo functional studies (Scott et al. J Clin Invest. 2004 Jan;113:274-84; Sidhu et al. Circulation. 2005 Jan;111:21-9; Folmes et al. Circ Cardiovasc Genet. 2009 Oct;2:457-66; Zhang et al. J Cardiol. 2013 Oct;62:241-8; Thorn et al. EJNMMI Res. 2013;3:48), and has been seen to segregate with disease in multiple unrelated families described to have Wolff-Parkinson-White syndrome, cardiac conduction system disease, and HCM, or some combination of those presentations (Gollob et al. N Engl J Med. 2001 Jun;344(24):1823-31; Arad et al. J Clin Invest. 2002 Feb;109(3):357-62; Sternick et al. J Cardiovasc Electrophysiol. 2006 Jul; 17(7):724-32; Charron et al. Europace. 2007 Aug;9:597-600; Tan et al. Circ Arrhythm Electrophysiol. 2008 Oct;1:276-81; Thevenon J et al. Europace, 2017 Apr;19:651-659). The p.R302P (c.905G>C) variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
CardioboostCm	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.49	T;.;.;.;.
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D;.
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D
MetaSVM	Pathogenic	0.87	D
MutationAssessor	Uncertain	2.1	M;.;.;.;.
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-6.8	D;D;D;D;D
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0050	D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		1.0	D;.;.;.;.
Vest4		0.98
MutPred		0.77		Loss of catalytic residue at R302 (P = 0.0572);.;.;.;.;
MVP		0.99
MPC		2.0
ClinPred		0.99	D
GERP RS		4.5
Varity_R		0.83
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs121908987; hg19: chr7-151273498;