NM_001005242.3(PKP2):c.2446-3A>G AND Arrhythmogenic right ventricular cardiomyopathy

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Jun 8, 2023
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:: RCV004004839.2

Allele description [Variation Report for NM_001005242.3(PKP2):c.2446-3A>G]

NM_001005242.3(PKP2):c.2446-3A>G

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.2446-3A>G

HGVS:

NC_000012.12:g.32792495T>C
NG_009000.1:g.109352A>G
NM_001005242.3:c.2446-3A>GMANE SELECT
NM_004572.4:c.2578-3A>G
LRG_398t1:c.2578-3A>G
LRG_398:g.109352A>G
NC_000012.11:g.32945429T>C
NM_004572.3:c.2578-3A>G

Links:

dbSNP: rs1956078300

NCBI 1000 Genomes Browser:

rs1956078300

Molecular consequence:

NM_001005242.3:c.2446-3A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_004572.4:c.2578-3A>G - intron variant - [Sequence Ontology: SO:0001627]

Observations:

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
SCV004832113	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Jun 8, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 25087486, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004832113

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Jun 8, 2023)

germline

clinical testing

PubMed (2)
[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	1	not provided	not provided	108544	not provided	clinical testing

Citations

PubMed

Functional assessment of potential splice site variants in arrhythmogenic right ventricular dysplasia/cardiomyopathy.

Groeneweg JA, Ummels A, Mulder M, Bikker H, van der Smagt JJ, van Mil AM, Homfray T, Post JG, Elvan A, van der Heijden JF, Houweling AC, Jongbloed JD, Wilde AA, van Tintelen JP, Hauer RN, Dooijes D.

Heart Rhythm. 2014 Nov;11(11):2010-7. doi: 10.1016/j.hrthm.2014.07.041. Epub 2014 Jul 31.

PubMed [citation]

PMID:: 25087486

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 All of Us Research Program, National Institutes of Health, SCV004832113.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (2)

Description

This variant causes an A to G nucleotide substitution at the -3 position of the last intron 13 of the PKP2 gene. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. A functional RNA study with a carrier individual have shown that this variant creates a new preferentially used splice acceptor site 2 nucleotides upstream of the native intron 13 splice acceptor (PMID: 25087486). The mutant transcript is out of frame and is expected to escape nonsense-mediated decay and be expressed as a protein containing altered C-terminal sequence. This variant has been reported in two related individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 25087486). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	108544	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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