7-151560610-C-T

Variant names:

• chr7-151560610-C-T
• rs121908991
• NM_016203.4:c.1592G>A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_016203.4(PRKAG2):​c.1592G>A​(p.Arg531Gln) 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 (★★). Synonymous variant affecting the same amino acid position (i.e. R531R) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PRKAG2 NM_016203.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 7.71

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 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987
• PP5: Variant 7-151560610-C-T is Pathogenic according to our data. 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. Variant chr7-151560610-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKAG2	NM_016203.4	c.1592G>A	p.Arg531Gln	missense_variant	Exon 15 of 16	ENST00000287878.9	NP_057287.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRKAG2	ENST00000287878.9	c.1592G>A	p.Arg531Gln	missense_variant	Exon 15 of 16	1	NM_016203.4	ENSP00000287878.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Lethal congenital glycogen storage disease of heart Pathogenic:4

May 03, 2019

Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 26, 2020

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene (OMIM; PMID 15877279). (N) 0107 - This gene is known to be associated with autosomal dominant disease (OMIM). (N) 0200 - Variant is predicted to result in a missense amino acid change from an arginine to a glutamine (exon 15). (N) 0251 - Variant is heterozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (P) 0600 - Variant is located in an annotated domain or motif (predicted ligand binding sites within the CBS domain). (N) 0703 - Comparable variants have moderate previous evidence for pathogenicity. Alternative changes within this residue, p.(Arg531Leu) and p.(Arg531Gly), have previous pathogenic reports in clinical cases (ClinVar). (P) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. This variant has previously been reported pathogenic in multiple individuals with severe infant onset hypertrophic cardiomyopathy (ClinVar; PMID: 28801758, 15877279). (P) 1002 - Moderate functional evidence supporting abnormal protein function. This variant has been shown to have loss of function effects resulting in enhanced downstream activity (PMID 15877279). (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -

May 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 531 of the PRKAG2 protein (p.Arg531Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy and/or nonlysosomal heart glycogenosis (PMID: 15877279, 25611685). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 6852). 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%. Experimental studies have shown that this missense change affects PRKAG2 function (PMID: 15877279). This variant disrupts the p.Arg531 amino acid residue in PRKAG2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11748095, 14722619, 27621313). 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. -

Jun 01, 2005

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:1

Mar 27, 2013

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Arg531Gln (CGG>CAG): c.1592 G>A in exon 15 of the PRKAG2 gene (NM_016203.3) The Arg531Gln mutation in the PRKAG2 gene has been reported in association with cardiomyopathy (Burwinkel B et al., 2005). This study identified Arg531Gln in three babies with severe congenital cardiomegaly and HCM and it was not identified in 190 control chromosomes. In one of the three reported infants, the Arg531Gln mutation was shown to further supporting its pathogenicity (Burwinkel B et al., 2005). Arg531Gln results in a semi-conservative amino acid substitution of a positively charged Arginine with a neutral, polar Glutamine at a position that is conserved across species. In silico analysis predicts Arg531Gln is damaging to the protein structure/function. Other missense mutations at this codon (Arg531Gly) and in a nearby codon (His530Arg) have been reported in association with HCM and WPW, and alter a functionally critical nucleotide binding site. In fact, functional studies have demonstrated that both Arg531Gln and Arg531Gly severely impair AMP and ATP binding and alter basal activity and phosphorylation of the AMP-activated protein kinase (Burwinkel B et al., 2005). Furthermore, The Arg531Gln mutation was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.In summary, Arg531Gln in the PRKAG2 gene is interpreted as a disease-causing mutation. The variant is found in HCM panel(s). -

Hypertrophic cardiomyopathy Pathogenic:1

Jul 18, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The Arg531Gln variant in PRKAG2 has been reported in 3 infants with fatal congen ital heart glycogenosis, occurring de novo in one case, and was absent in 190 co ntrol chromosomes (Burwinkel 2005). In addition, this variant has been identifie d by our laboratory in 4 infants with HCM (including one individual who also had LVNC and features of glycogen storage disease) and appears to have occurred de novo in 2 of these cases (only one parent was available in the third case). Bioc hemical characterization of the Arg531Gln variant showed that it has a significa nt impact on protein function (Burwinkel 2005). In summary, the Arg531Gln varian t meets our criteria for pathogenicity (http://pcpgm.partners.org/LMM) based on de novo occurrence and functional studies. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
CardioboostCm	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.85	D;.;.;.
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D;D;D
M_CAP	Pathogenic	0.41	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.6	H;.;.;.
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-3.7	D;D;D;D
REVEL	Pathogenic	0.97
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;.;.;.
Vest4		0.95
MutPred		0.95		Gain of catalytic residue at R531 (P = 0.1295);.;.;.;
MVP		0.98
MPC		1.8
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.87
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs121908991; hg19: chr7-151257696; COSMIC: COSV55223940; COSMIC: COSV55223940;