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

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Jan 27, 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:: RCV001177629.4

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:: Cardiomyopathy (CMYO)
Synonyms:: Cardiomyopathies
Identifiers:: MONDO: MONDO:0004994; MedGen: C0878544; Human Phenotype Ontology: HP:0001638

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001341870	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jan 27, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 18662195, 28807990, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001341870

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Jan 27, 2023)

germline

clinical testing

PubMed (3)
[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

Investigating the Genetic Causes of Sudden Unexpected Death in Children Through Targeted Next-Generation Sequencing Analysis.

Dewar LJ, Alcaide M, Fornika D, D'Amato L, Shafaatalab S, Stevens CM, Balachandra T, Phillips SM, Sanatani S, Morin RD, Tibbits GF.

Circ Cardiovasc Genet. 2017 Aug;10(4). doi:pii: e001738. 10.1161/CIRCGENETICS.116.001738.

PubMed [citation]

PMID:: 28807990

See all PubMed Citations (3)

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV001341870.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This missense variant replaces arginine with tryptophan at codon 635 of the PKP2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 18662195) and in three infants affected with sudden unexpected death (PMID: 28807990). This variant has been identified in 1/251288 chromosomes 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	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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