Variant classification is the final stage of variant
characterization. Classification includes assigning an interpretive category
representing clinical significance to each variant.
The ACMG categories rely heavily on the identification of novel vs. known variants which implies comparison to external variation databases. RUNES currently uses HGMD and dbSNP to fulfill this role, though the current state of available databases limits their utility. These existing databases are incomplete (do not contain many variants), or can contain misannotations (incorrect identification of variant) or mis-associations (association of common polymorphisms to disease) (Bell et. al).
The initial version of RUNES is unable to categorize any variants as Category 5 or Category 6, meaning that most novel variants without clear pathogenicity will end up as Category 4. It is expected that as these existing resources improve or as additional clinical grade databases become available this categorization will be updated to include these categories.
will receive a classification. RUNES uses categories recommended by
the American College of Medical Geneticists2 - these are listed
along with the criteria used for including a variant in each
||Previously reported, recognized cause of the
||HGMD variant type of 'Disease Mutant' dbSNP Snp
Clinical Significance of 'pathogenic'
||Novel, of a type expected to cause the
||loss of initiation
premature stop codon
disruption of stop codon
whole transcript deletion
disruption of splicing through deletion causing CDS/intron
overlap with splice donor or acceptor sites.
||Novel, may or may not be causal
disruption of polypyrimidine tract
overlap with 5' exonic, 5 ' flank or 3' exonic splice
||Novel, probably not causal of disease
||all variants not in categories 1 - 3
synonymous AA changes
overlap with 5' intronic or 3' flank splice contexts pyrimidine
substitutions in polypyrimidine tract, other intronic
dbSNP GMAF of greater than 0.02
||Known neutral variant
||Not known/expected to cause of disease but
associated with a clinical presentation