Identification of Misclassified ClinVar Variants via Disease Population Prevalence

Abstract

There is a significant interest in the standardized classification of human genetic variants. We used whole-genome sequence data from 10,495 unrelated individuals to contrast population frequency of pathogenic variants to the expected population prevalence of the disease. Analyses included the ACMG-recommended 59 gene-condition sets for incidental findings and 463 genes associated with 265 OrphaNet conditions. A total of 25,505 variants were used to identify patterns of inflation (i.e., excess genetic risk and misclassification). Inflation increases as the level of evidence supporting the pathogenic nature of the variant decreases. We observed up to 11.5% of genetic disorders with inflation in pathogenic variant sets and up to 92.3% for the variant set with conflicting interpretations. This improved to 7.7% and 57.7%, respectively, after filtering for disease-specific allele frequency. The patterns of inflation were replicated using public data from more than 138,000 genomes. The burden of rare variants was a main contributing factor of the observed inflation, indicating collective misclassified rare variants. We also analyzed the dynamics of re-classification of variant pathogenicity in ClinVar over time, which indicates progressive improvement in variant classification. The study shows that databases include a significant proportion of wrongly ascertained variants; however, it underscores the critical role of ClinVar to contrast claims and foster validation across submitters.

Keywords: ACMG; ClinVar; OrphaNet; pathogenic variant; penetrance; prevalence.

Figure 1

Genetic Risk in ACMG-59 Conditions Fold-change of observed genetic risk over expected population prevalence using ClinVar variant sets for the ACMG-59 conditions. Each point represents a condition; each condition may be represented in more than one set. The navy blue line at a fold-change of 10 (i.e., inflation) indicates a theoretical penetrance of 10%. Observations above this line are highly suggestive of misclassified variants. The boxplot shows median (horizontal line in the box), first and third quartile (lower and upper hinges of the box, respectively). The upper whisker extends from the hinge to the largest value no further than 1.5 ^∗ inter-quartile range (IQR) from the hinge. The lower whisker extends from the hinge to the smallest value at most 1.5 ^∗ IQR of the hinge. (A) Fold-change was calculated using variants per variant set: set 1 consists of variants with 2 or more ClinVar review stars (i.e., two or more submitters with assertion criteria, expert panel, and practice guideline); set 2 consists of variants with 1 star (i.e., one submitter with assertion criteria); set 3 consists of variants with 0 star (i.e., submitter with no assertion criteria submitted in ClinVar); set 4 consists of variants with conflicting interpretations of pathogenicity. (B) Fold-change was calculated by using variants cumulatively from each set; i.e., set 2 includes set 1 variants, set 3 includes set 1 and 2 variants, set 4 includes all variants. (C) Fold-change was re-calculated after variants were filtered for disease-specific minor allele frequency thresholds.

Figure 2

Genetic Risk in OrphaNet Conditions Fold-change of observed genetic risk over expected population prevalence using variant sets from ClinVar for the OrphaNet conditions. Each point represents a condition; each condition may be represented in more than one set. The navy blue line at a fold-change of 10 (i.e., inflation) indicates a theoretical penetrance of 10%. Observations above this line are highly suggestive of misclassified variants. The boxplot shows median (horizontal line in the box), first and third quartile (lower and upper hinges of the box, respectively). The upper whisker extends from the hinge to the largest value no further than 1.5 ^∗ inter-quartile range (IQR) from the hinge. The lower whisker extends from the hinge to the smallest value at most 1.5 ^∗ IQR of the hinge. (A) Fold-change was calculated using variants per variant set: set 1 consists of variants with 2 or more ClinVar review stars (i.e., two or more submitters with assertion criteria, expert panel, and practice guideline); set 2 consists of variants with 1 star (i.e., one submitter with assertion criteria); set 3 consists of variants with 0 star (i.e., submitter with no assertion criteria submitted in ClinVar); set 4 consists of variants with conflicting interpretations of pathogenicity. (B) Fold-change was calculated by using variants cumulatively from each set; i.e., set 2 includes set 1 variants, set 3 includes set 1 and 2 variants, set 4 includes all variants. (C) Fold-change was re-calculated after variants were filtered for disease-specific minor allele frequency thresholds.

Figure 3

Change in ClinVar Variant Classification from May 2016 to September 2017 In the study period, 7,615 ClinVar variants changed classification. Predominantly, variants were reclassified to “conflicting interpretation” (n = 5,867; 77%). Only 158 variants (2%) were reclassified as pathogenic or likely pathogenic. Thickness of the arrows corresponds to the number of variants reclassified.