rs730880978

chr7-151574892-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_016203.4(PRKAG2):c.1004T>C(p.Met335Thr) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,330 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. M335V) 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, splice_region
• Scores: Splicing: ADA: 0.004053
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:4
• 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 Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a hotspot region, there are 3 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRKAG2	NM_016203.4	c.1004T>C	p.Met335Thr	missense_variant, splice_region_variant	8/16	ENST00000287878.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRKAG2	ENST00000287878.9	c.1004T>C	p.Met335Thr	missense_variant, splice_region_variant	8/16	1	NM_016203.4	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461330 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727006

Gnomad4 AFR exome AF: 0.00

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Lethal congenital glycogen storage disease of heart Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 335 of the PRKAG2 protein (p.Met335Thr). 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: 18811822, 32646569; Invitae). ClinVar contains an entry for this variant (Variation ID: 181477). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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 specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Aug 19, 2016

The M335T variant has previously been reported in a 42 year-man with HCM and paroxysmal drug-resistant atrial fibrillation (Van Belle et al., 2008). In addition, this variant was found to segregate with disease in this man's father, who was reported to have the same phenotype (Van Belle et al., 2008). This variant 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. The M335T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, although the M335T variant has been observed in other unrelated individuals referred for HCM genetic testing at GeneDx, observation in these individuals, for whom segregation data is lacking, is not sufficient to determine the absolute pathogenicity of this variant. Furthermore, to our knowledge no studies have been performed to determine the functional effect of the M335T variant. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign. -

Cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Jan 16, 2019

Variant of Uncertain Significance due to insufficient evidence: This variant is located in the CBS domain 1 of the PRKAG2 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in two related individuals affected with hypertrophic cardiomyopathy and paroxysmal atrial fibrillation (PMID: 18811822). This variant is rare in the general population and has been identified in 0/277264 chromosomes by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the role of this variant in disease conclusively. -

not provided Uncertain:1

Uncertain significance, no assertion criteria provided

provider interpretation

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Sep 07, 2017

p.Met335Thr (c.1004T>C) in PRKAG2 (NM_016203.3) SCICD: variant of uncertain significance, probably disease causing. The rarity and case data support pathogenicity, however since we don't have specific or reliable phenotypic data several of the laboratory cases we can not be confident in pathogenicity. Cases: It has been seen in one published case with matching phenotype (van Belle et al) and several cases within private laboratory datasets without detail available on phenotype. Reference data: The variant is not listed in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Latino, and Ashkenazi descent. The average coverage at that site in gnomAD is >34x. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 14, 2023

The p.M335T variant (also known as c.1004T>C), located in coding exon 8 of the PRKAG2 gene, results from a T to C substitution at nucleotide position 1004. The methionine at codon 335 is replaced by threonine, an amino acid with similar properties. This alteration has been reported in a case report of an individual with hypertrophic cardiomyopathy (HCM) (Van Belle Y et al. Pacing Clin Electrophysiol, 2008 Oct;31:1358-61). Additionally, this alteration was detected in a HCM cohort; however, clinical details were limited (Harper AR et al. Nat Genet, 2021 Feb;53:135-142). 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	0.69
CardioboostCm	Benign	0.072
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.23
Cadd	Uncertain	25
Dann	Benign	0.94
DEOGEN2	Benign	0.12	T;.;.;.;.
Eigen	Benign	-0.075
Eigen_PC	Benign	0.040
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D;D;D;D;.
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.67	D;D;D;D;D
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Benign	1.4	L;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-3.0	D;D;D;D;D
REVEL	Pathogenic	0.69
Sift	Benign	0.25	T;T;T;T;T
Sift4G	Benign	0.59	T;T;T;T;T
Polyphen		0.16	B;.;.;.;.
Vest4		0.87
MutPred		0.47		Gain of relative solvent accessibility (P = 0.0479);.;.;.;.;
MVP		0.96
MPC		0.74
ClinPred		0.95	D
GERP RS		3.4
Varity_R		0.35
gMVP		0.78

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0041
dbscSNV1_RF	Benign	0.030
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: rs730880978; hg19: chr7-151271978;