NM_016203.4(PRKAG2):c.1366C>G (p.Arg456Gly) AND Lethal congenital glycogen storage disease of heart

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Dec 13, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001875905.6

Allele description [Variation Report for NM_016203.4(PRKAG2):c.1366C>G (p.Arg456Gly)]

NM_016203.4(PRKAG2):c.1366C>G (p.Arg456Gly)

Gene:

PRKAG2:protein kinase AMP-activated non-catalytic subunit gamma 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7q36.1

Genomic location:

Preferred name:

NM_016203.4(PRKAG2):c.1366C>G (p.Arg456Gly)

HGVS:

NC_000007.14:g.151565753G>C
NG_007486.2:g.316479C>G
NM_001040633.2:c.1234C>G
NM_001304527.2:c.991C>G
NM_001304531.2:c.643C>G
NM_001363698.2:c.994C>G
NM_016203.4:c.1366C>GMANE SELECT
NM_024429.2:c.643C>G
NP_001035723.1:p.Arg412Gly
NP_001291456.1:p.Arg331Gly
NP_001291460.1:p.Arg215Gly
NP_001350627.1:p.Arg332Gly
NP_057287.2:p.Arg456Gly
NP_077747.1:p.Arg215Gly
LRG_430t1:c.1366C>G
LRG_430:g.316479C>G
LRG_430p1:p.Arg456Gly
NC_000007.13:g.151262839G>C
NC_000007.13:g.151262839G>C
NG_007486.1:g.316478C>G
NM_016203.3:c.1366C>G

Protein change:

R215G

Links:

dbSNP: rs779098740

NCBI 1000 Genomes Browser:

rs779098740

Molecular consequence:

NM_001040633.2:c.1234C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001304527.2:c.991C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001304531.2:c.643C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001363698.2:c.994C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_016203.4:c.1366C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_024429.2:c.643C>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Lethal congenital glycogen storage disease of heart
Synonyms:: GLYCOGEN STORAGE DISEASE OF HEART; PHOSPHORYLASE KINASE DEFICIENCY OF HEART
Identifiers:: MONDO: MONDO:0009867; MedGen: C1849813; Orphanet: 439854; OMIM: 261740

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002188122	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Dec 13, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002188122

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Dec 13, 2023)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002188122.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 456 of the PRKAG2 protein (p.Arg456Gly). This variant is present in population databases (rs779098740, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with PRKAG2-related conditions. ClinVar contains an entry for this variant (Variation ID: 920060). 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%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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