Dutch genome diagnostic laboratories accelerated and improved variant interpretation and increased accuracy by sharing data

Abstract

Each year diagnostic laboratories in the Netherlands profile thousands of individuals for heritable disease using next‐generation sequencing (NGS). This requires pathogenicity classification of millions of DNA variants on the standard 5‐tier scale. To reduce time spent on data interpretation and increase data quality and reliability, the nine Dutch labs decided to publicly share their classifications. Variant classifications of nearly 100,000 unique variants were catalogued and compared in a centralized MOLGENIS database. Variants classified by more than one center were labeled as “consensus” when classifications agreed, and shared internationally with LOVD and ClinVar. When classifications opposed (LB/B vs. LP/P), they were labeled “conflicting”, while other nonconsensus observations were labeled “no consensus”. We assessed our classifications using the InterVar software to compare to ACMG 2015 guidelines, showing 99.7% overall consistency with only 0.3% discrepancies. Differences in classifications between Dutch labs or between Dutch labs and ACMG were mainly present in genes with low penetrance or for late onset disorders and highlight limitations of the current 5‐tier classification system. The data sharing boosted the quality of DNA diagnostics in Dutch labs, an initiative we hope will be followed internationally. Recently, a positive match with a case from outside our consortium resulted in a more definite disease diagnosis.

GJB2 and GJB6 Genetic Variant Curation in an Argentinean Non-Syndromic Hearing-Impaired Cohort

“…The curation of variants performed in the present work highlights the importance of specialized guidelines to analyze and interpret variants for the clinical use of databases. Moreover, it indicates the need of scientific community interaction and data sharing to avoid or reduce difficulties in variant curation [ 104 , 105 ]. Manual curation, although time consuming is strictly needed, as shown for the p.Met163Leu variant, which was originally interpreted as pathogenic for autosomal dominant HL by one submitter, and now reclassified to uncertain significance.…”

Truncating SRCAP variants outside the Floating-Harbor syndrome locus cause a distinct neurodevelopmental disorder with a specific DNA methylation signature

“…We focused on affected individuals with truncating variants because SRCAP is intolerant only to loss-of-function variants (pLI = 1) but not to missense variants (Z = 2.1). The individuals with SRCAP truncating variants outside the FLHS locus were identified and recruited through a collaborative network of research and diagnostic centers, the Dutch Genome Diagnostic Laboratories (VKGL) variant sharing database, 25 and by using MSSNG, 26 GeneMatcher, 27 DECIPHER, 28 and the Simons Simplex Collection (SSC). 29 Clinical and molecular data were provided by the individuals’ clinicians, which were compared to data previously described in the literature from cohorts of individuals with FLHS.…”

CAPICE: a computational method for Consequence-Agnostic Pathogenicity Interpretation of Clinical Exome variations

“…An overview of the training and benchmark datasets can be found in Table 1. Training and benchmark data on neutral and pathogenic variants were derived from vcf files from the ClinVar database [17], dated 02 January 2019; from the VKGL data share consortium [30]; from the GoNL data [31]; and from data used in a previous study [29]. From the ClinVar dataset, we collected variants reported by one or more submitters to have clear clinical significance, including pathogenic and likely pathogenic variants and neutral and likely neutral variants.…”