Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Laboratory for Molecular Medicine, |
RCV000038221 | SCV000061889 | uncertain significance | not specified | 2019-02-07 | criteria provided, single submitter | clinical testing | Variant classified as Uncertain Significance - Favor Benign. The Arg158Lys variant (PKP2) has been reported in one Asian individual with ARVD/C and was absent in 100 race matched controls (Qui 2009). In another study, the variant was absent in 93 ARVD/C probands but was present in 1/854 control chromosomes from a racially diverse but apparently healthy population (Kapplinger 2011). Identified in 0.085% of East Asian chromosomes in gnomAD. The presence of the variant in a single control is not sufficient to assume a benign riole as a presymptomatic status of this individual cannot be excluded. Arginine (Arg) at position 158 is conserved across mammals but not distant species, and computational analyses (PolyPhen2, SIFT, AlignGVGD) do not provide strong evidence for or against pathogenicity. In summary, the clinical significance of this variant cannot be determined with certainty at this time. |
| Invitae | RCV000865670 | SCV001006673 | likely benign | Arrhythmogenic right ventricular dysplasia 9 | 2024-01-22 | criteria provided, single submitter | clinical testing | |
| Color Diagnostics, |
RCV001178858 | SCV001343411 | likely benign | Cardiomyopathy | 2020-09-10 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000038221 | SCV002570779 | likely benign | not specified | 2022-07-05 | criteria provided, single submitter | clinical testing | Variant summary: PKP2 c.473G>A (p.Arg158Lys) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6.4e-05 in 251440 control chromosomes, predominantly at a frequency of 0.00087 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is slightly higher than the estimated maximal expected allele frequency for a pathogenic variant in PKP2 causing Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy phenotype (0.00065), suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely benign n=2, VUS n=1). Based on the evidence outlined above, the variant was classified as likely benign. |