NM_016203.4(PRKAG2):c.620C>G (p.Ser207Cys) AND Lethal congenital glycogen storage disease of heart

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Dec 2, 2021
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000371199.18

Allele description [Variation Report for NM_016203.4(PRKAG2):c.620C>G (p.Ser207Cys)]

NM_016203.4(PRKAG2):c.620C>G (p.Ser207Cys)

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.620C>G (p.Ser207Cys)

HGVS:

NC_000007.14:g.151675484G>C
NG_007486.2:g.206748C>G
NM_001040633.2:c.488C>G
NM_001304527.2:c.248C>G
NM_001363698.2:c.248C>G
NM_016203.4:c.620C>GMANE SELECT
NP_001035723.1:p.Ser163Cys
NP_001291456.1:p.Ser83Cys
NP_001350627.1:p.Ser83Cys
NP_057287.2:p.Ser207Cys
LRG_430t1:c.620C>G
LRG_430:g.206748C>G
LRG_430p1:p.Ser207Cys
NC_000007.13:g.151372570G>C
NG_007486.1:g.206747C>G
NM_016203.3:c.620C>G
c.620C>G

Protein change:

S163C

Links:

dbSNP: rs397517277

NCBI 1000 Genomes Browser:

rs397517277

Molecular consequence:

NM_001040633.2:c.488C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001304527.2:c.248C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001363698.2:c.248C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_016203.4:c.620C>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
SCV000467636	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification 20161018)	Uncertain significance (Jun 14, 2016)	germline	clinical testing	ICSL_Variant_Classification_20161018.pdf, Citation Link,
SCV001214023	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Dec 2, 2021)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 27532257, 32746448, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000467636

Illumina Laboratory Services, Illumina

criteria provided, single submitter

(ICSL Variant Classification 20161018)

Uncertain significance
(Jun 14, 2016)

germline

clinical testing

ICSL_Variant_Classification_20161018.pdf,

Citation Link,

SCV001214023

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Dec 2, 2021)

germline

clinical testing

PubMed (3)
[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

Genetic variant burden and adverse outcomes in pediatric cardiomyopathy.

Burstein DS, Gaynor JW, Griffis H, Ritter A, Connor MJO, Rossano JW, Lin KY, Ahrens-Nicklas RC.

Pediatr Res. 2021 May;89(6):1470-1476. doi: 10.1038/s41390-020-1101-5. Epub 2020 Aug 3.

PubMed [citation]

PMID:: 32746448
PMCID:: PMC8256333

See all PubMed Citations (3)

Details of each submission

From Illumina Laboratory Services, Illumina, SCV000467636.2

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

#	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

From Invitae, SCV001214023.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

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. 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 not expected to disrupt PRKAG2 protein function. ClinVar contains an entry for this variant (Variation ID: 45729). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 27532257, 32746448). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 207 of the PRKAG2 protein (p.Ser207Cys).

#	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: May 1, 2024

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