Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Laboratory for Molecular Medicine, |
RCV000038214 | SCV000061882 | uncertain significance | not specified | 2015-03-06 | criteria provided, single submitter | clinical testing | proposed classification - variant undergoing re-assessment, contact laboratory |
| Invitae | RCV000686767 | SCV000814300 | uncertain significance | Arrhythmogenic right ventricular dysplasia 9 | 2024-01-25 | criteria provided, single submitter | clinical testing | This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 854 of the PKP2 protein (p.His854Tyr). This variant is present in population databases (rs397517023, gnomAD 0.003%). This missense change has been observed in individual(s) with cardiomyopathy (PMID: 27000522). ClinVar contains an entry for this variant (Variation ID: 45073). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. |
| Color Diagnostics, |
RCV001188111 | SCV001355083 | uncertain significance | Cardiomyopathy | 2023-02-09 | criteria provided, single submitter | clinical testing | This missense variant replaces histidine with tyrosine at codon 854 of the PKP2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with arrhythmogenic right ventricular cardiomyopathy and sudden death (PMID:27000522). Three additional members of the family were clinically unaffected carriers. This variant has been identified in 7/282850 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. |
| Fulgent Genetics, |
RCV000686767 | SCV002789418 | uncertain significance | Arrhythmogenic right ventricular dysplasia 9 | 2021-12-23 | criteria provided, single submitter | clinical testing | |
| Ambry Genetics | RCV003162334 | SCV003866219 | uncertain significance | Cardiovascular phenotype | 2023-01-31 | criteria provided, single submitter | clinical testing | The p.H854Y variant (also known as c.2560C>T), located in coding exon 13 of the PKP2 gene, results from a C to T substitution at nucleotide position 2560. The histidine at codon 854 is replaced by tyrosine, an amino acid with similar properties. This alteration has been reported in a sudden unexplained death cohort and an arrhythmogenic right ventricular cardiomyopathy (ARVC) cohort; however, clinical details were limited in both cases (Cann F et al. Clin Genet, 2017 Jan;91:22-29; Dries AM et al. Genet Med, 2021 Oct;23:1961-1968). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |