7-151560611-G-C

Variant names:

• chr7-151560611-G-C
• rs121908990
• NM_016203.4:c.1591C>G

Variant summary

Our verdict is Pathogenic. The variant received 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
• Publications: 30 publications found

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 Gene-Disease associations (from GenCC):

• hypertrophic cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• hypertrophic cardiomyopathy 6

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• PRKAG2-related cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• lethal congenital glycogen storage disease of heart

  Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia, Genomics England PanelApp
• Wolff-Parkinson-White syndrome

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain 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-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 45701.
• 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 VariationId is 6851.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016203.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKAG2	NM_016203.4	MANE Select	c.1591C>G	p.Arg531Gly	missense	Exon 15 of 16	NP_057287.2
	PRKAG2	NM_001407021.1		c.1591C>G	p.Arg531Gly	missense	Exon 15 of 15	NP_001393950.1
	PRKAG2	NM_001407022.1		c.1588C>G	p.Arg530Gly	missense	Exon 15 of 15	NP_001393951.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKAG2	ENST00000287878.9	TSL:1 MANE Select	c.1591C>G	p.Arg531Gly	missense	Exon 15 of 16	ENSP00000287878.3
	PRKAG2	ENST00000392801.6	TSL:1	c.1459C>G	p.Arg487Gly	missense	Exon 15 of 16	ENSP00000376549.2
	PRKAG2	ENST00000418337.6	TSL:1	c.868C>G	p.Arg290Gly	missense	Exon 11 of 12	ENSP00000387386.2

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

Dec 18, 2001

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Cardiovascular phenotype Pathogenic:1

Jul 24, 2018

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 v4.9

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
M_CAP	Pathogenic	0.42	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.6	H
PhyloP100		4.4
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-6.4	D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	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
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121908990; hg19: chr7-151257697;