NM_001005242.3(PKP2):c.2471T>A (p.Val824Asp) AND Arrhythmogenic right ventricular dysplasia 9

This record was updated by the submitter. Please see the current version.

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Aug 13, 2021
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:: RCV000692916.5

Allele description

NM_001005242.3(PKP2):c.2471T>A (p.Val824Asp)

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.2471T>A (p.Val824Asp)

HGVS:

NC_000012.12:g.32792467A>T
NG_009000.1:g.109380T>A
NM_001005242.3:c.2471T>AMANE SELECT
NM_004572.4:c.2603T>A
NP_001005242.2:p.Val824Asp
NP_004563.2:p.Val868Asp
NP_004563.2:p.Val868Asp
LRG_398t1:c.2603T>A
LRG_398:g.109380T>A
LRG_398p1:p.Val868Asp
NC_000012.11:g.32945401A>T
NM_004572.3:c.2603T>A

Protein change:

V824D

Links:

dbSNP: rs752195586

NCBI 1000 Genomes Browser:

rs752195586

Molecular consequence:

NM_001005242.3:c.2471T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_004572.4:c.2603T>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Arrhythmogenic right ventricular dysplasia 9 (ARVD9)
Synonyms:: ARRHYTHMOGENIC RIGHT VENTRICULAR DYSPLASIA, FAMILIAL, 9; Arrhythmogenic right ventricular cardiomyopathy, type 9; Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy 9
Identifiers:: MONDO: MONDO:0012180; MedGen: C1836906; OMIM: 609040

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000820765	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Aug 13, 2021)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 24981977, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000820765

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Aug 13, 2021)

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	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Next generation sequencing challenges in the analysis of cardiac sudden death due to arrhythmogenic disorders.

Brion M, Blanco-Verea A, Sobrino B, Santori M, Gil R, Ramos-Luis E, Martinez M, Amigo J, Carracedo A.

Electrophoresis. 2014 Nov;35(21-22):3111-6. doi: 10.1002/elps.201400148. Epub 2014 Aug 6.

PubMed [citation]

PMID:: 24981977

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Invitae, SCV000820765.3

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

Description

This sequence change replaces valine with aspartic acid at codon 868 of the PKP2 protein (p.Val868Asp). The valine residue is highly conserved and there is a large physicochemical difference between valine and aspartic acid. This variant is present in population databases (rs752195586, ExAC 0.001%). This missense change has been observed in individual(s) with sudden death (PMID: 24981977). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been 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	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Feb 7, 2023

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