Reduced penetrance of pathogenic ACMG variants in a deeply phenotyped cohort study and evaluation of ClinVar classification over time

Abstract

Purpose: We studied the penetrance of pathogenically classified variants in an elderly Dutch population from the Rotterdam Study, for which deep phenotyping is available. We screened the 59 actionable genes for which reporting of known pathogenic variants was recommended by the American College of Medical Genetics and Genomics (ACMG), and demonstrate that determining what constitutes a known pathogenic variant can be quite challenging. Methods: We defined "known pathogenic" as classified pathogenic by both ClinVar and the Human Gene Mutation Database (HGMD). In 2628 individuals, we performed exome sequencing and identified known pathogenic variants. We investigated the clinical records of carriers and evaluated clinical events during 25 years of follow-up for evidence of variant pathogenicity. Results: Of 3815 variants detected in the 59 ACMG genes, 17 variants were considered known pathogenic. For 14/17 variants the ClinVar classification had changed over time. Of 24 confirmed carriers of these variants, we observed at least one clinical event possibly caused by the variant in only three participants (13%). Conclusion: We show that the definition of "known pathogenic" is often unclear and should be approached carefully. Additionally variants marked as known pathogenic do not always have clinical impact on their carriers. Definition and classification of true (individual) expected pathogenic impact should be defined carefully.

Targeted Sequencing of 242 Clinically Important Genes in the Russian Population From the Ivanovo Region

“…When known pathogenic and novel or rare protein-truncating variants were considered together, the overall rate of confirmed phenotypes was about 19%, with maximum in the subset of novel PTVs. This is in overall agreement with the other studies: in the population cohort from the Rotterdam Study, there were 13% of the carriers of known pathogenic variants in the ACMG59 genes who had phenotype correlated with genotype (Van Rooij et al, 2020). The Rotterdam study was based on a larger sample size of 2,628 individuals and involved an in-depth analysis of the phenotypes.…”

“…This uncertainty is gradually decreasing as more studies evaluate the carrier status of pathogenic gene variants in general populations (Amendola et al, 2016;Wright et al, 2019;Van Rooij et al, 2020). Numerous papers reported the prevalence of known and expected pathogenic variants in various populations, for example, Dutch (Haer-Wigman et al, 2019;Van Rooij et al, 2020), Qatari (Jain et al, 2018), Korean (Kwak et al, 2017), Australian (Lacaze et al, 2020), British (Van Hout et al, 2020), and Taiwanese (Kuo et al, 2020). The present study investigates the incidental findings of pathogenic variants in 28 genes from the ACMG59 list in the Russian population from the Ivanovo region.…”

“…The next-generation sequencing projects of the last decade revealed the complicated spectrum of rare and ultra-rare allelic variation in most human genes (Tennessen et al, 2012;Lek et al, 2016;Van Hout et al, 2020). The sequencing of large population cohorts greatly enriched our understanding of the prevalence of presumably pathogenic variants in reportedly healthy people (Dorschner et al, 2013;Amendola et al, 2015;Dewey et al, 2016) and initiated studies aimed at reviewing the implied pathogenicity of genetic variants (Dewey et al, 2014;Shah et al, 2018) and penetrance of variants classified as pathogenic (Cooper et al, 2013;Chen et al, 2016;Wright et al, 2019;Van Rooij et al, 2020). This activity was shaped by the standards and guidelines for the classification of sequence variants using criteria informed by expert opinion developed by The American College of Medical Genetics and Genomics (ACMG) (Richards et al, 2015;Nykamp et al, 2017).…”

“…However, limited information on the penetrance of many variants even in this relatively small set of genes makes interpretation challenging. This uncertainty is gradually decreasing as more studies evaluate the carrier status of pathogenic gene variants in general populations (Amendola et al, 2016;Wright et al, 2019;Van Rooij et al, 2020). Numerous papers reported the prevalence of known and expected pathogenic variants in various populations, for example, Dutch (Haer-Wigman et al, 2019;Van Rooij et al, 2020), Qatari (Jain et al, 2018), Korean (Kwak et al, 2017), Australian (Lacaze et al, 2020), British (Van Hout et al, 2020), and Taiwanese (Kuo et al, 2020).…”

GPCards: An integrated database of genotype–phenotype correlations in human genetic diseases

“…Furthermore, we also encourage users to upload anonymized genotype–phenotype data to GPCards. Second, genotype–phenotype correlations in GPCards could be used to assist in diagnosis but not as diagnostic criteria, due to the following three points: (i) pathogenic variants may later be identified as non-pathogenic, as previous reported [80] ; (ii) some of the reported pathogenic have not been functionally validated in cell and animal experiments; (iii) many genes and variants may present incomplete penetrance.…”