Variant Categorization

CSA reports the following four categories of variants, using a subset of the American College of Medical Genetics and Genomics (ACMG) variant categories:

Variant categorization in CSA

Category

Subcategory

Description

Cat1

Rare variants previously reported as pathogenic in HGMD, ClinVar, and/or OMIM

Cat1B

Different position and different call, same codon, same amino acid consequence of  a Cat1 variant

Cat1C

Different position and different call, same codon, different amino acid consequence of a Cat1 variant

Cat1D

Reported as unknown in ClinVar, OMIM, or HGMD

Cat2

Rare variants previously unreported (novel) but expected to lead to truncated protein, including the introduction of a stop codon, loss of a stop codon, loss of the initiation codon (ATG), alteration of the sequence at a splice junction (2 base region at the 3’ and 5’ ends of an intron), or shift of translational reading frame; high-impact variants according to VEP classification, and therefore likely causative

Cat3

Rare and missense variants previously unreported (novel) that may or may not be causative of the disorder, also called “Variants of uncertain significance” (VUS); moderate-impact variants according to VEP classification, and therfore likely causative; subcategorized as Cat3A and Cat3B depending on impact score (the highest score of either Polyphen2 or (1-Sorting Intolerant from Tolerant (SIFT))

Cat3A

Missense variants with an impact score >= 0.9; variants likely to affect splicing

Cat3B

Missense variants with an impact score < 0.9; variants unlikely to affect splicing

Cat4

Previously unreported variants that are unlikely to be disease-causing due to high allele frequency; variants observed to be homozygous in any of the controls; for example, synonymous or intronic variants unlikely to affect splicing

Cat1, Cat2, and Cat3 categories include variants with an allele frequency lower the threshold that was defined in reportSettings. By convention, these variants are considered “rare” (see also popAlleleFreq).

Because of their potential role in disease, Cat1 and Cat2 variants are always reported in the Candidate Genes and All Variants tabs and subtabs of the variant listing regardless of their allele frequencies or VEP classification, and are therefore protected from filtering on these tabs (see also Advanced Report Tabs).

ACMG categorization of each sequence variant is assigned according to the following ordered list of tests:

  1. Evaluate the variant to determine if it meets ACMG Cat4 criteria. If not, go to step 2.

  2. Evaluate the variant to determine if it meets Cat1 criteria. If not Cat1, go to step 3.

  3. Evaluate the variant to determine if it meets Cat1B criteria. If not, go to step 4.

  4. Evaluate the variant to determine if it meets Cat1C criteria. If not, go to step 5.

  5. Evaluate the variant to determine if it meets Cat1D criteria. If not, go to step 6.

  6. Evaluate the variant to determine if it meets Cat2 criteria. If not, go to step 7.

  7. Evaluate the variant to determine if it meets Cat3A criteria. If not, go to step 8.

  8. Remaining variants are assigned to Cat3B.

../_images/variantPrioritization.png

Variant categorization scheme used by CSA

References

  • Richards CS, Bale S, Bellissimo DB, Das S, Grody WW, Hegde MR, Lyon E, Ward BE. ACMG recommendations for standards for interpretation and reporting of sequence variations: Revisions 2007. Genetics in Medicine. 2008 Apr;10(4):294-300.

  • Kingsmore SF, Dinwiddie DL, Miller NA, Soden SE, Saunders CJ, The Children’s Mercy Genomic Medicine Team. Adopting orphans: comprehensive genetic testing of Mendelian diseases of childhood by next-generation sequencing. Expert review of molecular diagnostics. 2011;11(8):855-868. doi:10.1586/erm.11.70.