7-151560611-G-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_016203.4(PRKAG2):c.1591C>G(p.Arg531Gly) variant causes a missense change. 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. R531L) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PRKAG2 NM_016203.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 4.35

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 12 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 chr7-151560610-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 6852.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985
• PP5: Variant 7-151560611-G-C is Pathogenic according to our data. Variant chr7-151560611-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 6851.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRKAG2	NM_016203.4	c.1591C>G	p.Arg531Gly	missense_variant	15/16	ENST00000287878.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRKAG2	ENST00000287878.9	c.1591C>G	p.Arg531Gly	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:2

Revision: criteria provided, single submitter

Submissions by phenotype

Wolff-Parkinson-White syndrome, childhood-onset Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 18, 2001

- -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 24, 2018

The p.R531G pathogenic mutation (also known as c.1591C>G), located in coding exon 15 of the PRKAG2 gene, results from a C to G substitution at nucleotide position 1591. The arginine at codon 531 is replaced by glycine, an amino acid with dissimilar properties, and is located in a cystathione beta-synthase (CBS) domain. This variant has been described in a family with multiple affected individuals showing a combination of findings, including early age of onset, syncope, Wolff-Parkinson-White (WPW) syndrome, ventricular pre-excitation, and atrial fibrillation (Gollob MH et al. Circulation, 2001 Dec;104:3030-3). Mouse models with this mutation have been show to develop WPW syndrome and cardiac hypertrophy (Yang X et al. J. Biol. Chem., 2016 Nov;291:23428-23439). An alternate amino acid substitution at this position, p.R531Q (c.1592G>A), has been detected in congenital cardiomegaly cases with increased glycogen concentrations in tissues, hypertrophic cardiomyopathy (HCM), Wolff-Parkinson-White syndrome and/or other abnormal ECG findings, including several reportedly de novo cases (Burwinkel B et al. Am. J. Hum. Genet., 2005 Jun;76:1034-49; Alfares AA et al. Genet. Med., 2015 Nov;17:880-8). Based on internal structural assessment, this alteration results in loss of specific AMP recognition interactions (Xiao B et al. Nat Commun, 2013;4:3017). Additional functional studies have demonstrated impaired AMP/ATP binding, although the exact physiological impact of this finding has not been confirmed (Scott JW et al. J. Clin. Invest., 2004 Jan;113:274-84; Burwinkel B et al. Am. J. Hum. Genet., 2005 Jun;76:1034-49). 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	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
Cadd	Pathogenic	28
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D;.;.;.
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Pathogenic	0.42	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.6	H;.;.;.
MutationTaster	Benign	1.0	A;A;A;A;A
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-6.4	D;D;D;D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;.;.;.
Vest4		0.96
MutPred		0.93		Loss of stability (P = 0.0314);.;.;.;
MVP		0.98
MPC		1.9
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.96
gMVP		0.99

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: rs121908990; hg19: chr7-151257697;