rs267606976

Positions:

• chr7-151564203-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

The NM_016203.4(PRKAG2):​c.1459T>C​(p.Tyr487His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,848 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y487C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PRKAG2 NM_016203.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:2
• Conservation: PhyloP100: 9.09

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 Likely_pathogenic. Variant got 7 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, 8 uncertain in NM_016203.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.931
• PP5: Variant 7-151564203-A-G is Pathogenic according to our data. Variant chr7-151564203-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 6853.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRKAG2	NM_016203.4	c.1459T>C	p.Tyr487His	missense_variant	14/16	ENST00000287878.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRKAG2	ENST00000287878.9	c.1459T>C	p.Tyr487His	missense_variant	14/16	1	NM_016203.4	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461848 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727230

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.00209 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cardiomyopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jul 19, 2018

Variant summary: PRKAG2 c.1459T>C (p.Tyr487His) results in a conservative amino acid change located in the CBS domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 246266 control chromosomes (gnomAD). The variant, c.1459T>C, has been reported in the literature in a family with two affected siblings. These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as "pathogenic." Zhang_2013 indicates "Mutations recognized thus far include His142Arg, Arg302Gln, His383Arg, Thr400Asn,Tyr487His, Asn488Ile, Gln506Lys, Arg531Gly, Ser548Pro, andInsLeu351 [210]. These mutations invariably cluster within theBateman domain [the region defined as the cystathionine beta-synthase (CBS) domains] of the PRKAG2 gene." Therefore, suggesting the domain is important for proper PRKAG2 protein function. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Hypertrophic cardiomyopathy 6 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 27, 2005

- -

Lethal congenital glycogen storage disease of heart Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 29, 2023

This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 487 of the PRKAG2 protein (p.Tyr487His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 15673802, 32746448; Invitae). ClinVar contains an entry for this variant (Variation ID: 6853). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PRKAG2 protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jun 23, 2022

Reported as pathogenic in 1/338 children with HCM or DCM, however, the patient also harbored an SCN1A variant (Burstein et al., 2021); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26729852, 28550180, 23778007, 17332438, 15877279, 29593177, 25997934, 25422142, 28431061, 16275868, 32746448, 15673802) -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 03, 2021

The p.Y487H variant (also known as c.1459T>C), located in coding exon 14 of the PRKAG2 gene, results from a T to C substitution at nucleotide position 1459. The tyrosine at codon 487 is replaced by histidine, an amino acid with similar properties. This alteration has been reporting in a hypertrophic cardiomyopathy (HCM) cohort in two family members with borderline left ventricular wall thickness and a shortened PR interval on electrocardiogram (ECG) (Arad M et al. N Engl J Med, 2005 Jan;352:362-72). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

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	0.46
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.59	D;.;.;.
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.93	D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.8	M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-4.7	D;D;D;D
REVEL	Pathogenic	0.93
Sift	Uncertain	0.015	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;.;.;.
Vest4		0.90
MutPred		0.82		Gain of disorder (P = 0.0671);.;.;.;
MVP		0.97
MPC		1.7
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.59
gMVP		0.89

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: rs267606976; hg19: chr7-151261289;