Total submissions: 14
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000766577 | SCV000236247 | uncertain significance | not provided | 2023-01-27 | criteria provided, single submitter | clinical testing | Reported in one family with ARVC (Adler et al., 2016), in one patient with sudden infant death (SIDS) (Neubauer et al., 2017), one patient with DCM (Forleo et al., 2017), and two patients referred for Brugada syndrome (Di Resta et al., 2015); however, additional clinical information was not provided; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21636032, 28074886, 26220970, 32906206, 28750076, 26743238, 34033898, 35932045) |
Invitae | RCV000415669 | SCV000638879 | uncertain significance | Arrhythmogenic right ventricular dysplasia 9 | 2024-01-21 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 695 of the PKP2 protein (p.Arg695Cys). This variant is present in population databases (rs199583774, gnomAD 0.04%). This missense change has been observed in individual(s) with clinical features of PKP2-related conditions (PMID: 26220970, 26743238, 28074886, 28750076, 36178741). This variant is also known as c.C1951T (p.R651C). ClinVar contains an entry for this variant (Variation ID: 45056). 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. |
Ambry Genetics | RCV000620572 | SCV000737866 | uncertain significance | Cardiovascular phenotype | 2022-11-14 | criteria provided, single submitter | clinical testing | The c.2083C>T (p.R695C) alteration is located in exon 10 (coding exon 10) of the PKP2 gene. This alteration results from a C to T substitution at nucleotide position 2083, causing the arginine (R) at amino acid position 695 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. |
Illumina Laboratory Services, |
RCV000415669 | SCV001266716 | uncertain significance | Arrhythmogenic right ventricular dysplasia 9 | 2018-01-13 | criteria provided, single submitter | clinical testing | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. |
CHEO Genetics Diagnostic Laboratory, |
RCV001171160 | SCV001333845 | uncertain significance | Cardiomyopathy | 2017-11-14 | criteria provided, single submitter | clinical testing | |
Color Diagnostics, |
RCV001171160 | SCV001357607 | uncertain significance | Cardiomyopathy | 2023-12-08 | criteria provided, single submitter | clinical testing | This missense variant replaces arginine with cysteine at codon 695 of the PKP2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in three related individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 26743238), one individual affected with dilated cardiomyopathy (PMID: 28750076), and one individual affected with idiopathic ventricular tachycardia (PMID: 33552729). This variant has also been identified in 36/282782 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. |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV000038196 | SCV001572437 | uncertain significance | not specified | 2021-11-07 | criteria provided, single submitter | clinical testing | Variant summary: PKP2 c.2083C>T (p.Arg695Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00013 in 251388 control chromosomes. This frequency is not higher than the maximum expected for a pathogenic variant in PKP2 causing Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (ARVC) (0.00065), allowing no conclusion about variant significance. However, in certain subpopulations the variant was found at a higher frequency, e.g. in Southern Europeans control individuals the variant occurs with a frequency of 0.00087, suggesting that the variant maybe a benign polymorphism. The variant, c.2083C>T, has been reported in the literature in individuals affected with various cardiac phenotypes, including ARVC (Adler_2016), Brugada syndrome (Di Resta_2015), dilated cardiomyopathy (Forleo_2017) and sudden infant death syndrome (SIDS) (Neubauer_2017), however it was also found in healthy controls (Kapplinger_2011, Narang_2020). 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. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. |
Al Jalila Children's Genomics Center, |
RCV000038196 | SCV001984312 | uncertain significance | not specified | 2019-12-23 | criteria provided, single submitter | clinical testing | |
Fulgent Genetics, |
RCV000415669 | SCV002796920 | uncertain significance | Arrhythmogenic right ventricular dysplasia 9 | 2021-12-23 | criteria provided, single submitter | clinical testing | |
Mayo Clinic Laboratories, |
RCV000766577 | SCV004226317 | uncertain significance | not provided | 2023-04-20 | criteria provided, single submitter | clinical testing | |
All of Us Research Program, |
RCV003996377 | SCV004845946 | uncertain significance | Arrhythmogenic right ventricular cardiomyopathy | 2024-01-11 | criteria provided, single submitter | clinical testing | This missense variant replaces arginine with cysteine at codon 695 of the PKP2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in three related individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 26743238), one individual affected with dilated cardiomyopathy (PMID: 28750076), and one individual affected with idiopathic ventricular tachycardia (PMID: 33552729). This variant has also been identified in 36/282782 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, |
RCV000038196 | SCV000061863 | uncertain significance | not specified | 2008-12-30 | no assertion criteria provided | clinical testing | |
Blueprint Genetics | RCV000157416 | SCV000207156 | uncertain significance | Primary dilated cardiomyopathy | 2014-09-29 | no assertion criteria provided | clinical testing | |
Knight Diagnostic Laboratories, |
RCV000415669 | SCV000493778 | uncertain significance | Arrhythmogenic right ventricular dysplasia 9 | 2016-01-27 | no assertion criteria provided | clinical testing |