NM_001005242.3(PKP2):c.1378G>A (p.Gly460Ser) AND Arrhythmogenic right ventricular cardiomyopathy

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Jul 16, 2018
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:: RCV004018392.2

Allele description [Variation Report for NM_001005242.3(PKP2):c.1378G>A (p.Gly460Ser)]

NM_001005242.3(PKP2):c.1378G>A (p.Gly460Ser)

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.1378G>A (p.Gly460Ser)

HGVS:

NC_000012.12:g.32850766C>T
NG_009000.1:g.51081G>A
NM_001005242.3:c.1378G>AMANE SELECT
NM_001407155.1:c.1378G>A
NM_001407156.1:c.1378G>A
NM_001407157.1:c.1378G>A
NM_001407158.1:c.1051G>A
NM_001407159.1:c.1051G>A
NM_001407160.1:c.1051G>A
NM_001407161.1:c.1378G>A
NM_001407162.1:c.1051G>A
NM_004572.4:c.1378G>A
NP_001005242.2:p.Gly460Ser
NP_001394084.1:p.Gly460Ser
NP_001394085.1:p.Gly460Ser
NP_001394086.1:p.Asp460Asn
NP_001394087.1:p.Gly351Ser
NP_001394088.1:p.Gly351Ser
NP_001394089.1:p.Gly351Ser
NP_001394090.1:p.Gly460Ser
NP_001394091.1:p.Gly351Ser
NP_004563.2:p.Asp460Asn
NP_004563.2:p.Asp460Asn
LRG_398t1:c.1378G>A
LRG_398:g.51081G>A
LRG_398p1:p.Asp460Asn
NC_000012.11:g.33003700C>T
NM_004572.3:c.1378G>A

Protein change:

D460N

Molecular consequence:

NM_001005242.3:c.1378G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407155.1:c.1378G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407156.1:c.1378G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407157.1:c.1378G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407158.1:c.1051G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407159.1:c.1051G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407160.1:c.1051G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407161.1:c.1378G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407162.1:c.1051G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_004572.4:c.1378G>A - missense variant - [Sequence Ontology: SO:0001583]

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
SCV004848225	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely Pathogenic (Jul 16, 2018)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 20525856, 24967631, 25087486, 21606396, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004848225

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely Pathogenic
(Jul 16, 2018)

germline

clinical testing

PubMed (5)
[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

Lower than expected desmosomal gene mutation prevalence in endurance athletes with complex ventricular arrhythmias of right ventricular origin.

La Gerche A, Robberecht C, Kuiperi C, Nuyens D, Willems R, de Ravel T, Matthijs G, Heidbüchel H.

Heart. 2010 Aug;96(16):1268-74. doi: 10.1136/hrt.2009.189621. Epub 2010 Jun 4.

PubMed [citation]

PMID:: 20525856

Stop-gain mutations in PKP2 are associated with a later age of onset of arrhythmogenic right ventricular cardiomyopathy.

Alcalde M, Campuzano O, Berne P, García-Pavía P, Doltra A, Arbelo E, Sarquella-Brugada G, Iglesias A, Alonso-Pulpon L, Brugada J, Brugada R.

PLoS One. 2014;9(6):e100560. doi: 10.1371/journal.pone.0100560.

PubMed [citation]

PMID:: 24967631
PMCID:: PMC4072667

See all PubMed Citations (5)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV004848225.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

The p.Asp460Asn variant in PKP2 has been reported in at least 5 individuals with ARVC and segregated with disease in 2 affected relatives from 2 families (La Gerche 2010, Cox 2011, Munoz Calero 2012, Alcalde 2014, Groeneweg 2014). It was absent from large population studies. This variant is located in the last base of exon 5, which is part of the 5’ splice region. RNA studies and computational tools suggest an impact to splicing by activating a cryptic splice site, resulting in an out-of-frame transcript that is likely degraded by NMD (Groeneweg 2014). In summary, although additional studies are required to fully establish its clinical significance, the p.Asp460Asn variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PM4, PS3_Supporting, PS4_Supporting.

#	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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