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Pediatric Genomic Medicine ACMG Classification
Pediatric Genomic Medicine ACMG Classification

Variant classification is the final stage of variant characterization. Classification includes assigning an interpretive category representing clinical significance to each variant. 

ACMG Categories

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).

Database Enhancement

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.

Variant Classifications

Every variant 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 category:

Category Description Criteria
1 Previously reported, recognized cause of the disorder HGMD variant type of 'Disease Mutant' dbSNP Snp Clinical Significance of 'pathogenic'
2 Novel, of a type expected to cause the disorder loss of initiation
premature stop codon
disruption of stop codon
whole transcript deletion
frameshifting in/del
disruption of splicing through deletion causing CDS/intron fusion
overlap with splice donor or acceptor sites.
3 Novel, may or may not be causal non-synonymous substitution
in-frame in/del
disruption of polypyrimidine tract
overlap with 5' exonic, 5 ' flank or 3' exonic splice contexts
4 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 variants
dbSNP GMAF of greater than 0.02
5 Known neutral variant not used
6 Not known/expected to cause of disease but associated with a clinical presentation not used

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