ClinVar Miner

Submissions for variant NM_001005242.3(PKP2):c.224-3C>G (rs786204387)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000621077 SCV000736352 uncertain significance Cardiovascular phenotype 2019-07-30 criteria provided, single submitter clinical testing Insufficient evidence
Invitae RCV000686191 SCV000813696 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 9 2018-04-10 criteria provided, single submitter clinical testing This sequence change falls in intron 1 of the PKP2 gene. It does not directly change the encoded amino acid sequence of the PKP2 protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 23671136, 24125834). ClinVar contains an entry for this variant (Variation ID: 188652). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000168927 SCV000280412 uncertain significance not specified 2015-06-11 no assertion criteria provided clinical testing Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. IVS1-3 C>G (c.224-3 C>G) in PKP2 (NM_004572.3) Based on the fact that all the known cases are Chinese and we lack a large general population dataset on Asians, we classify the variant as of uncertain significance, probably disease causing. More ancestry-matched control data would be helpful in assessing pathogenicity. In total the variant has been seen in at least 2, possibly 3 unrelated cases of ARVC, all Chinese (not including the patient's case). We have seen the variant in one other individual with ARVC in our clinic. That individual also happens to be of Chinese ancestry. In the other family with ARVC we are for with this variant it was also present in the paternal first cousin with ARVC. Bao et al (2013) observed the variant in 1 of 90 unrelated individuals with ARVC in their Chinese cohort who underwent analysis of 9 genes associated with ARVC. The GeneDx report also notes it was included in a paper from the Hopkins registry, however that case is almost certainly the patient, since she is enrolled in their registry (Bhonsale et al 2013). It is not listed in ClinVar (as of October 15th, 2014). I found a 2011 abstract online from a Chinese group in Guangdong (none of the affiliations for the Bao et al group were in Guangdong). Unfortuantely it is in Chinese, but using google translate it appears they are reporting on an ARVC patient with this variant ( and the paper - About 10% of published ARVC-associated variants are splicing variants in PKP2. Based on in silico analysis performed by GeneDx with three different programs that predict the impact of variants on splicing, this variant is expected to interfere with normal splicing. Another splicing variant affecting the same intron (IVS1+1G>A) has been reported in a patient with ARVC (Fressart et al 2010). In total this variant has not been seen in ~7527 controls or individuals from publicly available general population datasets, though only a minority of these match the patient's ancestry (360). IVS1-3C>G was absent in GeneDx’s 300 Caucasian and African-American controls. Unfortunately they have no Asian controls (matching the patient’s ancestry and the ancestry of the other cases). It was also not seen in a panel of 427 control individuals recently published by Kapplinger et al (2011). That included 127 individuals of asian ancestry. It is not listed in the 1000 genomes data (as of January 2nd, 2013). Specifically, the variant was not observed in low coverage (4-5x) sequencing of 60 Chinese individuals in that study (as of January 10th, 2012). Bao et al (2013) did not see it in 300 Chinese controls. In addition, it is not listed in dbSNP (as of January 2nd, 2012). The variant is not currently listed in the NHLBI Exome Sequencing Project dataset, which includes variant calls on ~6500 Caucasian and African American individuals (as of January 2nd, 2013). Note that this dataset does not match the patient's ancestry. LL _ also has TNNT2 VUS

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