Um die Kausalität einer genetischen Variante in Bezug auf einen Phänotyp festzustellen, ist es notwendig, ausreichende wissenschaftliche Beweise zu erhalten. Die von der ACMG vorgeschlagene Pathogenitätsklassifizierung sieht 5 Klassifizierungskategorien vor: Gutartig, wahrscheinlich gutartig, Variante mit ungewisser Bedeutung, wahrscheinlich pathogen und pathogen. Diese Kategorien werden auf der Grundlage der Wahrscheinlichkeit definiert, dass ein kausaler Zusammenhang zwischen der erkannten Variante und dem Phänotyp besteht, sodass eine als wahrscheinlich pathogen eingestufte Variante mit einer Wahrscheinlichkeit von 90 % pathogen ist und eine als pathogen eingestufte Variante mit einer Wahrscheinlichkeit von 99 % tatsächlich pathogen ist. Das bedeutet auch, dass die Klassifizierung einer Variante als VSI bedeutet, dass die Wahrscheinlichkeit, dass die Variante pathogen ist, irgendwo zwischen 11 und 89 % liegt.
Es wurde außerdem ein System zur Analyse der verschiedenen Arten von Beweisen vorgeschlagen, die aus Daten aus Bevölkerungsstudien, Daten aus Funktionsanalysen, In-silico-Vorhersagen oder Segregationsstudien stammen, und sie nach dem relativen Gewicht jedes Datentyps bei der Zuschreibung der Kausalität klassifiziert (sehr starke, starke, mäßige, unterstützende oder nicht ausreichende Beweise für sich genommen).
Es gibt mehrere Datenbanken, in denen die Pathogenität der in einer Sequenzierungsstudie identifizierten Varianten eingesehen werden kann, sofern diese zuvor in der Literatur beschrieben wurden und Untersuchungen zur Kausalität durchgeführt wurden. ClinGen ist die von der FDA für diesen Zweck zugelassene Datenbank.
Für den Fall, dass die Varianten noch nicht untersucht wurden, müssen Bevölkerungsdatenbanken sowohl für gesunde Menschen als auch für pathogene Varianten sowie andere Arten von Beweisen überprüft werden. Varsome ist ein Web-Tool, das mehrere Datenbanken (einschließlich ClinGen) nutzt, um eine automatisierte Interpretation gemäß ACMG-Kriterien bereitzustellen.
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1.
MacArthur DG, Manolio TA, Dimmock DP, Rehm HL, Shendure J, Abecasis GR, et al. Guidelines for investigating causality of sequence variants in human disease. Nature [Internet]. 2014 Abril [cited 2015 June 23];508(7497):469–76. Available from: http://www.nature.com/nature/journal/v508/n7497/full/nature13127.html
1.
Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med [Internet]. 2015 May [cited 2016 Sept 6];17(5):405–24. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4544753/