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NM_001005242.3(PKP2):c.964G>T (p.Gly322Cys) AND not specified

Germline classification:
Conflicting classifications of pathogenicity (2 submissions)
Last evaluated:
Dec 18, 2023
Review status:
criteria provided, conflicting classifications
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:
RCV000183732.9

Allele description [Variation Report for NM_001005242.3(PKP2):c.964G>T (p.Gly322Cys)]

NM_001005242.3(PKP2):c.964G>T (p.Gly322Cys)

Gene:
PKP2:plakophilin 2 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
12p11.21
Genomic location:
Preferred name:
NM_001005242.3(PKP2):c.964G>T (p.Gly322Cys)
Other names:
p.G322C:GGC>TGC
HGVS:
  • NC_000012.12:g.32877916C>A
  • NG_009000.1:g.23931G>T
  • NM_001005242.3:c.964G>TMANE SELECT
  • NM_004572.4:c.964G>T
  • NP_001005242.2:p.Gly322Cys
  • NP_001005242.2:p.Gly322Cys
  • NP_004563.2:p.Gly322Cys
  • NP_004563.2:p.Gly322Cys
  • LRG_398t1:c.964G>T
  • LRG_398:g.23931G>T
  • LRG_398p1:p.Gly322Cys
  • NC_000012.11:g.33030850C>A
  • NM_001005242.2:c.964G>T
  • NM_004572.3:c.964G>T
Protein change:
G322C
Links:
dbSNP: rs200069860
NCBI 1000 Genomes Browser:
rs200069860
Molecular consequence:
  • NM_001005242.3:c.964G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_004572.4:c.964G>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:
AllHighlyPenetrant
Identifiers:
MedGen: CN169374

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000747979Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute
criteria provided, single submitter

(ACMG Guidelines, 2015)
Uncertain significance
(Mar 1, 2017)
germlineclinical testing

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

SCV000918019Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)
Likely benign
(Dec 18, 2023)
germlineclinical testing

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

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee.

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753

Novel genotype-phenotype associations demonstrated by high-throughput sequencing in patients with hypertrophic cardiomyopathy.

Lopes LR, Syrris P, Guttmann OP, O'Mahony C, Tang HC, Dalageorgou C, Jenkins S, Hubank M, Monserrat L, McKenna WJ, Plagnol V, Elliott PM.

Heart. 2015 Feb;101(4):294-301. doi: 10.1136/heartjnl-2014-306387. Epub 2014 Oct 28.

PubMed [citation]
PMID:
25351510
PMCID:
PMC4345808
See all PubMed Citations (3)

Details of each submission

From Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute, SCV000747979.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000918019.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

Variant summary: PKP2 c.964G>T (p.Gly322Cys) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.5e-05 in 1614134 control chromosomes, predominantly at a frequency of 0.0011 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is at the estimated maximal expected allele frequency for a pathogenic variant in PKP2 causing Cardiomyopathy phenotype (0.0011), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.964G>T has been reported in the literature as a VUS in settings of multigene panel testing in at-least one individual with unexplained cardiac arrest and in another individual with hypertrophic cardiomyopathy (HCM) (example, Mellor_2017, Lopes_2015).. These report(s) do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 25351510, 28600387). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as likely benign (n=5) and VUS (n=2). Based on the evidence outlined above, the variant was classified as likely benign.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Jan 19, 2025