NM_001005242.3(PKP2):c.302G>A (p.Arg101His) AND not specified

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Sep 26, 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:: RCV000038217.8

Allele description [Variation Report for NM_001005242.3(PKP2):c.302G>A (p.Arg101His)]

NM_001005242.3(PKP2):c.302G>A (p.Arg101His)

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.302G>A (p.Arg101His)

HGVS:

NC_000012.12:g.32878954C>T
NG_009000.1:g.22893G>A
NM_001005242.3:c.302G>AMANE SELECT
NM_004572.4:c.302G>A
NP_001005242.2:p.Arg101His
NP_004563.2:p.Arg101His
NP_004563.2:p.Arg101His
LRG_398t1:c.302G>A
LRG_398:g.22893G>A
LRG_398p1:p.Arg101His
NC_000012.11:g.33031888C>T
NM_004572.3:c.302G>A
c.302G>A

Protein change:

R101H

Links:

dbSNP: rs149542398

NCBI 1000 Genomes Browser:

rs149542398

Molecular consequence:

NM_001005242.3:c.302G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_004572.4:c.302G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

Recent activity

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signal recognition particle receptor subunit alpha isoform X2 [Homo sapiens]
signal recognition particle receptor subunit alpha isoform X2 [Homo sapiens]
gi|1034575060|ref|XP_016873668.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000061885	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Likely benign (Jan 22, 2016)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 24503780, 20400443, 24033266
SCV004100157	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Uncertain significance (Sep 26, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 20400443, 23396983, 24503780, 26230511, 30821013 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000061885

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Likely benign
(Jan 22, 2016)

germline

clinical testing

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

SCV004100157

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Uncertain significance
(Sep 26, 2023)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

Citation Link

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
not provided	germline	not provided	4	3	not provided	not provided	not provided	clinical testing

Citations

PubMed

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

Desmosomal gene analysis in arrhythmogenic right ventricular dysplasia/cardiomyopathy: spectrum of mutations and clinical impact in practice.

Fressart V, Duthoit G, Donal E, Probst V, Deharo JC, Chevalier P, Klug D, Dubourg O, Delacretaz E, Cosnay P, Scanu P, Extramiana F, Keller D, Hidden-Lucet F, Simon F, Bessirard V, Roux-Buisson N, Hebert JL, Azarine A, Casset-Senon D, Rouzet F, Lecarpentier Y, et al.

Europace. 2010 Jun;12(6):861-8. doi: 10.1093/europace/euq104. Epub 2010 Apr 16.

PubMed [citation]

PMID:: 20400443

See all PubMed Citations (6)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000061885.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	4	not provided	not provided	clinical testing	PubMed (3)

Description

p.Arg101His in exon 2 of PKP2: This variant is not expected to have clinical sig nificance due to a lack of conservation across species, including mammals. Of no te, the seal and 3 bat species have a histidine (His) at this position despite h igh nearby amino acid conservation. In addition, computational prediction tools do not suggest a high likelihood of impact to the protein. It has also been iden tified in 13/66714 European chromosomes by the Exome Aggregation Consortium (ExA C, http://exac.broadinstitute.org/; dbSNP rs149542398).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		4	not provided	3	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV004100157.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

Variant summary: PKP2 c.302G>A (p.Arg101His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00016 in 282808 control chromosomes (gnomAD), predominantly at a frequency of 0.00031 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in PKP2 causing Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (0.00016 vs 0.00065), allowing no conclusion about variant significance. c.302G>A has been reported in the literature in individuals affected with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (e.g Fressart_2010), Hypertrophic Cardiomyopathy (e.g. Lopes_2013), Dilated Cardiomyopathy (e.g. Pugh_2014) and Brugada Syndrome (e.g. Allegue_2015). These reports do not provide unequivocal conclusions about association of the variant with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 26230511, 30821013, 20400443, 23396983, 24503780). Ten ClinVar submitters have assessed the variant since 2014: five classified the variant as uncertain significance, and five as likely benign. Based on the evidence outlined above, the variant was classified as 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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