Functional evidence

Publications without functional evidence

Some publications in the field use molecular assays to validate that a variant in a non-coding sequence is causal for a disease. However, many publications by clinical groups do not include functional validation (this is usually not possible in clinical settings)-

In these cases, there are two major types of evidence.

Cosegregation

In clinical genetics, cosegregation refers to the inheritance of a specific genetic variant (or allele) along with a particular phenotype (disease or trait) within a family. Cosegregation is considered as a part of the Pathogenicity Classification of Genomic Variants (Jarvik and Browning, 2016). For the purposes of HRMDBQ, we will follow the conclusion of the authors about cosegregation (if no explicit statement is made, we will consider cosegregation to be present if more than one family member with the disease is shown to have the variant(s) as expected for the mode or inheritance, or a spontaneous patient has a de novo variant). Importantly, if there is evidence of non-segregation in a publication, then we should not include the variant in our curation.

Clinical phenotype

If a non-coding variant is identified in an individual with clinical manifestations of the disease associated with the corresponding gene, this can be considered to be clinical evidence for the pathogenicity.

Comparability

If a variant is located in a certain non-coding region where other bona fide non-coding variants are located, this can be considered to provide additional evidence.

HRMDBQ does not attempt to quantify the evidnece for pathogenicity as presented in publications. Instead it records author statements and allows users to draw their own conclusions.