NM_016203.4(PRKAG2):c.1436T>C (p.Ile479Thr) AND Lethal congenital glycogen storage disease of heart

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Apr 29, 2019
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:: RCV001223603.2

Allele description [Variation Report for NM_016203.4(PRKAG2):c.1436T>C (p.Ile479Thr)]

NM_016203.4(PRKAG2):c.1436T>C (p.Ile479Thr)

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.1436T>C (p.Ile479Thr)

HGVS:

NC_000007.14:g.151565347A>G
NG_007486.2:g.316885T>C
NM_001040633.2:c.1304T>C
NM_001304527.2:c.1061T>C
NM_001304531.2:c.713T>C
NM_001363698.2:c.1064T>C
NM_016203.4:c.1436T>CMANE SELECT
NM_024429.2:c.713T>C
NP_001035723.1:p.Ile435Thr
NP_001291456.1:p.Ile354Thr
NP_001291460.1:p.Ile238Thr
NP_001350627.1:p.Ile355Thr
NP_057287.2:p.Ile479Thr
NP_077747.1:p.Ile238Thr
LRG_430t1:c.1436T>C
LRG_430:g.316885T>C
LRG_430p1:p.Ile479Thr
NC_000007.13:g.151262433A>G
NG_007486.1:g.316884T>C
NM_016203.3:c.1436T>C

Protein change:

I238T

Links:

dbSNP: rs1806004431

NCBI 1000 Genomes Browser:

rs1806004431

Molecular consequence:

NM_001040633.2:c.1304T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001304527.2:c.1061T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001304531.2:c.713T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001363698.2:c.1064T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_016203.4:c.1436T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_024429.2:c.713T>C - 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
SCV001395759	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Apr 29, 2019)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 27532257, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001395759

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Apr 29, 2019)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

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

Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples.

Walsh R, Thomson KL, Ware JS, Funke BH, Woodley J, McGuire KJ, Mazzarotto F, Blair E, Seller A, Taylor JC, Minikel EV, Exome Aggregation Consortium, MacArthur DG, Farrall M, Cook SA, Watkins H.

Genet Med. 2017 Feb;19(2):192-203. doi: 10.1038/gim.2016.90. Epub 2016 Aug 17.

PubMed [citation]

PMID:: 27532257
PMCID:: PMC5116235

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, SCV001395759.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change replaces isoleucine with threonine at codon 479 of the PRKAG2 protein (p.Ile479Thr). The isoleucine residue is highly conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with hypertrophic cardiomyopathy (PMID: 27532257). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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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