NM_016203.4(PRKAG2):c.1006G>A (p.Val336Ile) AND not specified

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Aug 9, 2013
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:: RCV000155991.6

Allele description [Variation Report for NM_016203.4(PRKAG2):c.1006G>A (p.Val336Ile)]

NM_016203.4(PRKAG2):c.1006G>A (p.Val336Ile)

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.1006G>A (p.Val336Ile)

Other names:

p.V336I:GTA>ATA

HGVS:

NC_000007.14:g.151572709C>T
NG_007486.2:g.309523G>A
NM_001040633.2:c.874G>A
NM_001304527.2:c.631G>A
NM_001304531.2:c.283G>A
NM_001363698.2:c.634G>A
NM_016203.4:c.1006G>AMANE SELECT
NM_024429.2:c.283G>A
NP_001035723.1:p.Val292Ile
NP_001035723.1:p.Val292Ile
NP_001291456.1:p.Val211Ile
NP_001291460.1:p.Val95Ile
NP_001350627.1:p.Val212Ile
NP_057287.2:p.Val336Ile
NP_077747.1:p.Val95Ile
LRG_430t1:c.1006G>A
LRG_430:g.309523G>A
LRG_430p1:p.Val336Ile
NC_000007.13:g.151269795C>T
NG_007486.1:g.309522G>A
NM_001040633.1:c.874G>A
NM_016203.3:c.1006G>A

Protein change:

V211I

Links:

dbSNP: rs727504707

NCBI 1000 Genomes Browser:

rs727504707

Molecular consequence:

NM_001040633.2:c.874G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001304527.2:c.631G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001304531.2:c.283G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001363698.2:c.634G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_016203.4:c.1006G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_024429.2:c.283G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000205703	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Uncertain significance (Aug 9, 2013)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000280421	Stanford Center for Inherited Cardiovascular Disease, Stanford University	no assertion criteria provided	Uncertain significance (May 30, 2014)	germline	clinical testing

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000205703

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Uncertain significance
(Aug 9, 2013)

germline

clinical testing

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

SCV000280421

Stanford Center for Inherited Cardiovascular Disease, Stanford University

no assertion criteria provided

Uncertain significance
(May 30, 2014)

germline

clinical testing

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	2	1	not provided	not provided	not provided	clinical testing

Citations

PubMed

A systematic approach to assessing the clinical significance of genetic variants.

Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, Funke BH, Rehm HL, Lebo MS.

Clin Genet. 2013 Nov;84(5):453-63. doi: 10.1111/cge.12257.

PubMed [citation]

PMID:: 24033266
PMCID:: PMC3995020

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000205703.5

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

Description

The Val336Ile variant in PRKAG2 has not been reported in individuals with cardio myopathy or in large population studies. It is located in the CBS domain region of the PRKAG2 protein, where all pathogenic PRKAG2 variants have been identified to date (Oliveira 2003). Valine (Val) at position 336 is highly conserved in ma mmals and across evolutionarily distant species. However, additional computation al analyses (biochemical amino acid properties, AlignGVGD, PolyPhen2, and SIFT) suggest that the Val336Ile variant may not impact the protein, though this infor mation is not predictive enough to rule out pathogenicity. This variant is locat ed in the first base of the exon, which is part of the 3? splice region. Computa tional tools do not suggest an impact to splicing; however, this information is not predictive enough to DETERMINE/RULE OUT pathogenicity. In summary, additiona l information is needed to fully assess the clinical significance of this varian t.

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

From Stanford Center for Inherited Cardiovascular Disease, Stanford University, SCV000280421.1

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

Description

Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Val336Ile (c.1006G>A) in the PRKAG2 gene. This variant is novel. In silico analysis with PolyPhen-2 predicts the variant to be benign. Mutation Taster predicts this variant to be disease-causing, noting that the alteration is within a used splice site and is likely to disturb normal splicing. Val336Ile results in a conservative amino acid substitution of one non-polar amino acid with another. The valine at codon 336 is mostly conserved across species, although in Celegans and Dmelanogaster it is reported as alanine and glutamic acid, respectively. Neighboring amino acids are conserved. GeneDx reports that no mutations in nearby residues have been reported in HGMD in association with Wolff-Parkinson-White syndrome or cardiomyopathy. In total the variant has not been seen in ~6,500 published controls and individuals from publicly available population datasets. There is no variation at codon 336 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6,500 Caucasian and African American individuals (as of 7/13/13). Note that this dataset does not completely match the patient's ancestry. There is also no variation at this codon listed in dbSNP or 1000 genomes (as of 7/13/13). GeneDx did not give control data.

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

Last Updated: Sep 29, 2024

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