Total submissions: 8
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000483764 | SCV000568236 | likely pathogenic | not provided | 2017-07-12 | criteria provided, single submitter | clinical testing | This five base pair deletion has been reported previously in the Human Gene Mutation Database and the Arrhythmogenic Right Ventricular Cardiomyopathy database (Stenson et al., 2014; Van et al., 2009). The c.1440_1444delTCCCA variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This variant causes a shift in reading frame starting at codon Asparagine 480, changing it to a Lysine, and creating a premature stop codon at position 20 of the new reading frame, denoted p.Asn480LysfsX20. This variant is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. Other frameshift variants in the PKP2 gene have been reported in HGMD in association with ARVC (Stenson et al., 2014). |
Invitae | RCV001069896 | SCV001235094 | pathogenic | Arrhythmogenic right ventricular dysplasia 9 | 2022-11-01 | criteria provided, single submitter | clinical testing | This variant is present in population databases (rs775995156, gnomAD 0.002%). This sequence change creates a premature translational stop signal (p.Asn480Lysfs*20) in the PKP2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PKP2 are known to be pathogenic (PMID: 15489853, 23911551). This premature translational stop signal has been observed in individual(s) with arrhythmogenic right ventricular cardiomyopathy (PMID: 25157032). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 419977). |
Color Diagnostics, |
RCV001184322 | SCV001350273 | uncertain significance | Cardiomyopathy | 2022-12-02 | criteria provided, single submitter | clinical testing | This variant deletes 5 nucleotides in exon 6 of the PKP2b transcript (ENST00000070846 | NM_004572), creating a frameshift and premature translation stop signal. This exon 6 is alternately spliced out and is absent in the PKP2a transcript, the predominant isoform in the heart (ENST00000340811 | NM_001005242, PMID 21378009). Therefore, it is likely that a functional PKP2 gene product is expressed in the heart, despite the presence of this variant. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in three individuals affected with arrhythmogenic right ventricular cardiomyopathy, including two from the same family who also carried a pathogenic variant in the DSP gene (PMID: 25157032, 28588093). This variant has been identified in 3/271396 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. |
Baylor Genetics | RCV001069896 | SCV004041413 | likely pathogenic | Arrhythmogenic right ventricular dysplasia 9 | 2023-02-28 | criteria provided, single submitter | clinical testing | |
All of Us Research Program, |
RCV004003318 | SCV004846398 | uncertain significance | Arrhythmogenic right ventricular cardiomyopathy | 2023-02-15 | criteria provided, single submitter | clinical testing | This variant deletes 5 nucleotides in exon 6 of the PKP2b transcript (ENST00000070846 | NM_004572), creating a frameshift and premature translation stop signal. This exon 6 is alternately spliced out and is absent in the PKP2a transcript, the predominant isoform in the heart (ENST00000340811 | NM_001005242, PMID 21378009). Therefore, it is likely that a functional PKP2 gene product is expressed in the heart, despite the presence of this variant. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in three individuals affected with arrhythmogenic right ventricular cardiomyopathy, including two from the same family who also carried a pathogenic variant in the DSP gene (PMID: 25157032, 28588093). This variant has been identified in 3/271396 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. |
Laboratory for Molecular Medicine, |
RCV000483764 | SCV004848170 | uncertain significance | not provided | 2018-04-13 | criteria provided, single submitter | clinical testing | The p.Asn480fs variant in PKP2 has been reported in 2 individuals with ARVC, and segregated with disease in 1 affected family member from one family (Brun 2014, www.arvcdatabase.info). However, both individuals also carried other pathogenic variants in genes that could explain their disease. This variant has also been reported by other clinical laboratories in ClinVar (Variation ID# 419977) and has been identified in 3/123052 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs775995156). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 480 and leads to a premature termination codon 20 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. While heterozygous loss of function is an established disease mechanism in individuals with ARVC, this variant is located in an exon that is alternatively spliced and is not present in the dominant transcript in the heart (Gandjbakhch 2011). In summary, the clinical significance of the p.Asn480fs variant is uncertain. |
Gharavi Laboratory, |
RCV000483764 | SCV000809447 | pathogenic | not provided | 2018-09-16 | no assertion criteria provided | research | |
Cardiology unit, |
RCV001069896 | SCV002577350 | likely pathogenic | Arrhythmogenic right ventricular dysplasia 9 | 2022-09-27 | no assertion criteria provided | clinical testing |