NM_001005242.3(PKP2):c.12del (p.Gly5fs) AND Arrhythmogenic right ventricular cardiomyopathy

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: May 6, 2016
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:: RCV004018334.2

Allele description [Variation Report for NM_001005242.3(PKP2):c.12del (p.Gly5fs)]

NM_001005242.3(PKP2):c.12del (p.Gly5fs)

Gene:

PKP2:plakophilin 2 [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

12p11.21

Genomic location:

Preferred name:

NM_001005242.3(PKP2):c.12del (p.Gly5fs)

HGVS:

NC_000012.12:g.32896724del
NG_009000.1:g.5127del
NG_188275.1:g.49del
NM_001005242.3:c.12delMANE SELECT
NM_001407155.1:c.12del
NM_001407156.1:c.12del
NM_001407157.1:c.12del
NM_001407158.1:c.-815del
NM_001407159.1:c.-579del
NM_001407160.1:c.-579del
NM_001407161.1:c.12del
NM_001407162.1:c.-815del
NM_004572.4:c.12del
NP_001005242.2:p.Gly5fs
NP_001394084.1:p.Gly5fs
NP_001394085.1:p.Gly5fs
NP_001394086.1:p.Gly5fs
NP_001394090.1:p.Gly5fs
NP_004563.2:p.Gly5Alafs
NP_004563.2:p.Gly5fs
LRG_398t1:c.8del
LRG_398:g.5127del
LRG_398p1:p.Gly5Alafs
NC_000012.11:g.33049658del
NC_000012.12:g.32896720delG
NM_004572.3:c.8delC

Protein change:

G5fs

Molecular consequence:

NM_001407158.1:c.-815del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001407159.1:c.-579del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001407160.1:c.-579del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001407162.1:c.-815del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001005242.3:c.12del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001407155.1:c.12del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001407156.1:c.12del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001407157.1:c.12del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001407161.1:c.12del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_004572.4:c.12del - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Name:: Arrhythmogenic right ventricular cardiomyopathy (ARVD)
Synonyms:: Cardiomyopathy, ARVC; Arrhythmogenic right ventricular dysplasia
Identifiers:: MONDO: MONDO:0016587; MeSH: D019571; MedGen: C0349788

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004847963	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely Pathogenic (May 6, 2016)	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

SCV004847963

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely Pathogenic
(May 6, 2016)

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

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

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV004847963.1

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

Description

The p.Gly5fs (c.12delC) variant in PKP2 has not been previously reported, although the p.Gly5fs (c.14delG) variant has been identified in one individual with ARVC (LMM unpublished data). Data from large population studies is insufficient to assess the frequency of this variant. This frameshift variant is predicted to alter the protein’s amino acid sequence beginning at position 5 and lead to a premature termination codon 34 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of PKP2 function is an established disease mechanism in individuals with ARVC. In summary, although additional studies are required to fully establish its clinical significance, the p.Gly5fs variant is likely pathogenic.

#	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: Aug 4, 2024

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