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NM_001005242.3(PKP2):c.2018C>T (p.Pro673Leu) AND not specified

Germline classification:
Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:
May 17, 2023
Review status:
criteria provided, conflicting classifications
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:
RCV000599924.6

Allele description [Variation Report for NM_001005242.3(PKP2):c.2018C>T (p.Pro673Leu)]

NM_001005242.3(PKP2):c.2018C>T (p.Pro673Leu)

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.2018C>T (p.Pro673Leu)
HGVS:
  • NC_000012.12:g.32802552G>A
  • NG_009000.1:g.99295C>T
  • NM_001005242.3:c.2018C>TMANE SELECT
  • NM_004572.4:c.2150C>T
  • NP_001005242.2:p.Pro673Leu
  • NP_001005242.2:p.Pro673Leu
  • NP_004563.2:p.Pro717Leu
  • NP_004563.2:p.Pro717Leu
  • LRG_398t1:c.2150C>T
  • LRG_398:g.99295C>T
  • LRG_398p1:p.Pro717Leu
  • NC_000012.11:g.32955486G>A
  • NM_001005242.2:c.2018C>T
  • NM_004572.3:c.2150C>T
Protein change:
P673L
Links:
dbSNP: rs144018320
NCBI 1000 Genomes Browser:
rs144018320
Molecular consequence:
  • NM_001005242.3:c.2018C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_004572.4:c.2150C>T - missense variant - [Sequence Ontology: SO:0001583]
Observations:
1

Condition(s)

Synonyms:
AllHighlyPenetrant
Identifiers:
MedGen: CN169374

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000711404Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
criteria provided, single submitter

(LMM Criteria)		Uncertain significance
(May 16, 2017) 		germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV003933772Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)		Likely benign
(May 17, 2023) 		germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedgermlinenot provided11not providednot providednot providedclinical testing

Citations

PubMed

Age-dependent clinical and genetic characteristics in Japanese patients with arrhythmogenic right ventricular cardiomyopathy/dysplasia.

Ohno S, Nagaoka I, Fukuyama M, Kimura H, Itoh H, Makiyama T, Shimizu A, Horie M.

Circ J. 2013;77(6):1534-42. Epub 2013 Mar 20. Erratum in: Circ J. 2020;84(11):2123. doi: 10.1253/circj.CJ-66-0185.

PubMed [citation]
PMID:
23514727

A systematic approach to assessing the clinical significance of genetic variants.

Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, Funke BH, Rehm HL, Lebo MS.

Clin Genet. 2013 Nov;84(5):453-63. doi: 10.1111/cge.12257.

PubMed [citation]
PMID:
24033266
PMCID:
PMC3995020
See all PubMed Citations (5)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000711404.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (2)

Description

The p.Pro717Leu variant in PKP2 has been reported in 1 adult with arrhythmogenic right ventricular cardiomyopathy (AVRC) (Ohno 2013). This variant has also been identified in 0.1% (24/18868) of East Asian chromosomes by the Genome Aggregati on Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs144018320). This variant has been reported in Clinvar: (Variant ID 374966) with conflicting inter pretations. Computational prediction tools and conservation analysis suggest tha t the p.Pro717Leu variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical signifi cance of the p.Pro717Leu variant is uncertain.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot provided1not provided1not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV003933772.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

Variant summary: PKP2 c.2150C>T (p.Pro717Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0033 in 328700 control chromosomes, including 9 homozygotes (gnomAD and jMorp databases (Tadaka_2021). The observed variant frequency is approximately 5.02 fold of the estimated maximal expected allele frequency for a pathogenic variant in PKP2 causing Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy phenotype (0.00065), strongly suggesting that the variant is benign. c.2150C>T has been reported in the literature in individuals affected with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy, however without strong evidence for causality (e.g., Nakajima_2012, Wada_2017). These reports therefore do not provide unequivocal conclusions about association of the variant with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy. The following publications have been ascertained in the context of this evaluation (PMID: 33179747, 22214898, 29178656). Six ClinVar submitters (evaluation after 2014) have reported the variant with conflicting assessments: 3 classified the variant as likely benign, and 3 classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.

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

Last Updated: Sep 29, 2024