Create gene/disease specific classification criteria
Enter gene/disease specific parameters in the section above. Frequency thresholds are calculated from these values.
Select suitable evidence strengths from the drop down lists in the Pathogenic and Benign criteria tabs.
The display will automatically update to show which combinations of evidence are available to reach a certain class.
For deciding on the number of probands/segregation meoses, please refer to [3] in references.
The formulas used to calculate the frequency thresholds are based on [2] and [3] in references.
For additional information and to validate the frequency values please refer to this
allele frequency app.
Classify variants
Click on checkboxes to select corresponding evidence points for a given variant.
The display will automatically update when a variant is classified using an available criteria combination.
View detailed criteria by clicking on the Show details button.
Saving or sharing criteria/classification data
To save your work, click on the "Save/Share criteria" button and then store the link in your system (e.g. spreadsheet, browser bookmark, file/database).
The link can be shared with other users.
This application does not store any data itself.
Null variant in gene with established LOF as disease mechanism
Different nucleotide change (same amino acid) as a previously established pathogenic variant
De novo (both maternity and paternity confirmed) in a patient with disease and no family history
Functional studies of mammalian knock-in models supportive of a damaging effect on the gene or gene product
The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls or ExAC cohorts as proxy [3]:
Variant identified in ≥ probands with consistent phenotypes
Variant identified in ≥ probands with consistent phenotypes
Variant identified in ≥ probands with consistent phenotypes
Hotspot/established functional domain without benign variation - amino acids:
Detected in trans with a pathogenic variant (recessive)
Protein length changes due to in-frame deletions/insertions of any size in a nonrepeat region or stop-loss variants
Missense change at an amino acid residue where a different missense change previously established as pathogenic
Assumed de novo but without confirmation of paternity and maternity
Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease:
Variant segregates in ≥ meioses
Variant segregates in ≥ meioses
Variant segregates in ≥ meioses
Missense variant in a gene with a low rate of benign missense variation and where missense variants are a common mechanism of disease
Multiple lines of computational evidence support a deleterious effect on the gene or gene product
Phenotype specific for disease with single genetic etiology
Reputable source recently reports variant as pathogenic but the evidence is not available to perform an independent evaluation
Observed in healthy adult with full penetrance expected at an early age
Functional studies of mammalian knock-in models supportive of no damaging effect on protein function or splicing
Nonsegregation in affected members of a family
Missense variant in gene where only LOF causes disease
Observed as compound het (in trans) or double het in genes with overlapping function (e.g., sarcomere genes) without increased disease severity or observed in cis with a pathogenic variant in any inheritance pattern
In-frame deletions/insertions in a repetitive region without a known function
Multiple lines of computational evidence suggest no impact on gene or gene product
Variant found in a case with an alternate molecular basis for disease
Reputable source reports as benign
A silent variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site -AND- the nucleotide is not highly conserved
Examples are to show how this application works, not for clinical evaluation.
FAP
PJS
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