NM_001005242.3(PKP2):c.2108del (p.Lys703fs) AND not provided

Clinical significance:Likely pathogenic (Last evaluated: Nov 16, 2016)

Review status:(0/4) 0 stars out of maximum of 4 stars

no assertion criteria provided

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000786187.1

Allele description [Variation Report for NM_001005242.3(PKP2):c.2108del (p.Lys703fs)]

NM_001005242.3(PKP2):c.2108del (p.Lys703fs)

Gene:
PKP2:plakophilin 2 [Gene - OMIM - HGNC]
Variant type:
Deletion
Cytogenetic location:
12p11.21
Genomic location:
Preferred name:
NM_001005242.3(PKP2):c.2108del (p.Lys703fs)
HGVS:
  • NC_000012.12:g.32802466del
  • NG_009000.1:g.99385del
  • NM_001005242.3:c.2108delMANE SELECT
  • NM_004572.4:c.2240del
  • NP_001005242.2:p.Lys703fs
  • NP_004563.2:p.Lys747fs
  • LRG_398:g.99385del
  • NC_000012.11:g.32955400del
  • NM_004572.3:c.2240delA
Protein change:
K703fs
Links:
dbSNP: rs1565574709
NCBI 1000 Genomes Browser:
rs1565574709
Molecular consequence:
  • NM_001005242.3:c.2108del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_004572.4:c.2240del - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Identifiers:
MedGen: CN517202

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000924895Stanford Center for Inherited Cardiovascular Disease, Stanford Universityno assertion criteria providedLikely pathogenic
(Nov 16, 2016)
germlineprovider interpretation

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedprovider interpretation

Details of each submission

From Stanford Center for Inherited Cardiovascular Disease, Stanford University, SCV000924895.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedprovider interpretationnot provided

Description

Given the absence in controls and the variant type we consider this variant likely disease causing (aka likely pathogenic) and we do feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). This variant is absent in ClinVar (as of 11/16/2016), but other frameshift variants are reported as likely pathogenic or pathogenic. The variant has been seen in at least one unrelated cases of ARVC (not including our patient's family). No segregation studies available. Bao et al. (2013) reports one patient with ARVC who was found to have this variant, at the time novel. The study population comprised Chinese patients with either a definite, borderline, or possible diagnosis of ARVC. All participants had ventricular arrhythmias recorded, but no specific phenotypic individual for that patient was available. No segregation was included in this report. This variant is in exon 11. It creates a frameshift beginning with codon Lysine 747, changing this to an Arginine and creating a premature stop codon at position 7 of the new reading frame. It is expected to result in an abnormal, truncated protein. At least two dozen splice variants in this gene have been reported in association with ARVC (see http://www.arvcdatabase.info/). The majority of the disease-associated variants in PKP2 are splicing variants, frameshift, nonsense, or in-frame deletions. In one study 66 of 149 unrelated ARVC patients had such a variant (Cox et al 2011). In contrast, these variants are rare in the general population (Kapplinger et al 2011, ExAC, gnomAD). A study by Amr et al (2016) also supports the assumption that the PKP2 gene is intolerant to loss of function variation, reporting loss of function variants enriched in cases vs controls (OR: 114). There is no variation at codon 747 listed in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian (9,472 East Asian individuals in particular), European, Latino, and Ashkenazi descent. The average coverage at that site in gnomAD is 90x

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

Last Updated: Nov 27, 2021

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