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NM_001005242.3(PKP2):c.1740G>T (p.Glu580Asp) AND Arrhythmogenic right ventricular dysplasia 9

Germline classification:
Uncertain significance (2 submissions)
Last evaluated:
Dec 11, 2023
Review status:
2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts
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:
RCV000473176.13

Allele description [Variation Report for NM_001005242.3(PKP2):c.1740G>T (p.Glu580Asp)]

NM_001005242.3(PKP2):c.1740G>T (p.Glu580Asp)

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.1740G>T (p.Glu580Asp)
Other names:
p.E624D:GAG>GAT
HGVS:
  • NC_000012.12:g.32822566C>A
  • NG_009000.1:g.79281G>T
  • NM_001005242.3:c.1740G>TMANE SELECT
  • NM_004572.4:c.1872G>T
  • NP_001005242.2:p.Glu580Asp
  • NP_004563.2:p.Glu624Asp
  • NP_004563.2:p.Glu624Asp
  • LRG_398t1:c.1872G>T
  • LRG_398:g.79281G>T
  • LRG_398p1:p.Glu624Asp
  • NC_000012.11:g.32975500C>A
  • NM_004572.3:c.1872G>T
Protein change:
E580D
Links:
dbSNP: rs370219248
NCBI 1000 Genomes Browser:
rs370219248
Molecular consequence:
  • NM_001005242.3:c.1740G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_004572.4:c.1872G>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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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000545221Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Uncertain significance
(Dec 11, 2023)
germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV001269281Illumina Laboratory Services, Illumina
criteria provided, single submitter

(ICSL Variant Classification Criteria 13 December 2019)
Uncertain significance
(May 1, 2018)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Reevaluating the Genetic Contribution of Monogenic Dilated Cardiomyopathy.

Mazzarotto F, Tayal U, Buchan RJ, Midwinter W, Wilk A, Whiffin N, Govind R, Mazaika E, de Marvao A, Dawes TJW, Felkin LE, Ahmad M, Theotokis PI, Edwards E, Ing AY, Thomson KL, Chan LLH, Sim D, Baksi AJ, Pantazis A, Roberts AM, Watkins H, et al.

Circulation. 2020 Feb 4;141(5):387-398. doi: 10.1161/CIRCULATIONAHA.119.037661. Epub 2020 Jan 27.

PubMed [citation]
PMID:
31983221
PMCID:
PMC7004454

Systematic large-scale assessment of the genetic architecture of left ventricular noncompaction reveals diverse etiologies.

Mazzarotto F, Hawley MH, Beltrami M, Beekman L, de Marvao A, McGurk KA, Statton B, Boschi B, Girolami F, Roberts AM, Lodder EM, Allouba M, Romeih S, Aguib Y, Baksi AJ, Pantazis A, Prasad SK, Cerbai E, Yacoub MH, O'Regan DP, Cook SA, Ware JS, et al.

Genet Med. 2021 May;23(5):856-864. doi: 10.1038/s41436-020-01049-x. Epub 2021 Jan 26.

PubMed [citation]
PMID:
33500567
PMCID:
PMC8105165
See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000545221.7

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 624 of the PKP2 protein (p.Glu624Asp). This variant is present in population databases (rs370219248, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of PKP2-related conditions (PMID: 27930701, 31983221, 33500567). ClinVar contains an entry for this variant (Variation ID: 201999). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The aspartic acid amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Illumina Laboratory Services, Illumina, SCV001269281.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)

Description

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Jan 19, 2025