NM_001005242.3(PKP2):c.1771C>T (p.Arg591Trp) AND Arrhythmogenic right ventricular dysplasia 9

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Mar 24, 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:: RCV000555494.4

Allele description [Variation Report for NM_001005242.3(PKP2):c.1771C>T (p.Arg591Trp)]

NM_001005242.3(PKP2):c.1771C>T (p.Arg591Trp)

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.1771C>T (p.Arg591Trp)

HGVS:

NC_000012.12:g.32822535G>A
NG_009000.1:g.79312C>T
NM_001005242.3:c.1771C>TMANE SELECT
NM_004572.4:c.1903C>T
NP_001005242.2:p.Arg591Trp
NP_004563.2:p.Arg635Trp
NP_004563.2:p.Arg635Trp
LRG_398t1:c.1903C>T
LRG_398:g.79312C>T
LRG_398p1:p.Arg635Trp
NC_000012.11:g.32975469G>A
NM_004572.3:c.1903C>T

Protein change:

R591W

Links:

dbSNP: rs778928536

NCBI 1000 Genomes Browser:

rs778928536

Molecular consequence:

NM_001005242.3:c.1771C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_004572.4:c.1903C>T - 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
SCV000638873	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Mar 24, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 18662195, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000638873

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Mar 24, 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	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Abnormal connexin43 in arrhythmogenic right ventricular cardiomyopathy caused by plakophilin-2 mutations.

Fidler LM, Wilson GJ, Liu F, Cui X, Scherer SW, Taylor GP, Hamilton RM.

J Cell Mol Med. 2009 Oct;13(10):4219-28. doi: 10.1111/j.1582-4934.2008.00438.x. Epub 2008 Jul 26.

PubMed [citation]

PMID:: 18662195
PMCID:: PMC4496128

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 Labcorp Genetics (formerly Invitae), Labcorp, SCV000638873.3

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

Description

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. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 464415). This missense change has been observed in individual(s) with a PKP2-related disease (PMID: 18662195). This variant is present in population databases (rs778928536, gnomAD 0.0009%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 635 of the PKP2 protein (p.Arg635Trp).

#	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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