NM_001005242.3(PKP2):c.275T>A (p.Leu92Ter) AND Arrhythmogenic right ventricular cardiomyopathy

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Mar 18, 2019
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:: RCV004017466.1

Allele description [Variation Report for NM_001005242.3(PKP2):c.275T>A (p.Leu92Ter)]

NM_001005242.3(PKP2):c.275T>A (p.Leu92Ter)

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.275T>A (p.Leu92Ter)

Other names:

p.L92*:TTG>TAG

HGVS:

NC_000012.12:g.32878981A>T
NG_009000.1:g.22866T>A
NM_001005242.3:c.275T>AMANE SELECT
NM_004572.4:c.275T>A
NP_001005242.2:p.Leu92Ter
NP_004563.2:p.Leu92Ter
NP_004563.2:p.Leu92Ter
LRG_398t1:c.275T>A
LRG_398:g.22866T>A
LRG_398p1:p.Leu92Ter
NC_000012.11:g.33031915A>T
NM_004572.3:c.275T>A

Protein change:

L92*

Links:

dbSNP: rs763639737

NCBI 1000 Genomes Browser:

rs763639737

Molecular consequence:

NM_001005242.3:c.275T>A - nonsense - [Sequence Ontology: SO:0001587]
NM_004572.4:c.275T>A - nonsense - [Sequence Ontology: SO:0001587]

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
SCV004847667	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 18, 2019)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 27532257, 24832006, 20400443, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004847667

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Mar 18, 2019)

germline

clinical testing

PubMed (4)
[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

Sequenom MassARRAY approach in the arrhythmogenic right ventricular cardiomyopathy post-mortem setting: clinical and forensic implications.

Alcalde M, Campuzano O, Allegue C, Torres M, Arbelo E, Partemi S, Iglesias A, Brugada J, Oliva A, Carracedo A, Brugada R.

Int J Legal Med. 2015 Jan;129(1):1-10. doi: 10.1007/s00414-014-0996-y. Epub 2014 May 16.

PubMed [citation]

PMID:: 24832006

See all PubMed Citations (4)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV004847667.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

The p.Leu92X variant in PKP2 has been previously identified in 6 individuals with ARVC (Alcade 2015, Fressart 2010, Walsh 2017). This variant has been identified in 0.002% (2/113714) European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org) and in ClinVar (Variation ID 202026). This nonsense variant leads to a premature termination codon at position 92 which is 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, this variant meets criteria to be classified as pathogenic for ARVC in an autosomal dominant manner. ACMG/AMP Criteria applied: PVS1, PS4_Moderate, PM2.

#	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: Sep 29, 2024

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