Table 1 Pathogenicity criteria for two variants not reported in the ClinVar database according to ACMG standards and guidelines [11]
From: Case report: multiple UGT1A1 gene variants in a patient with Crigler-Najjar syndrome
Evidence of pathogenicity | Fulfilled criteria with explanation | g.5884G > T | g.11895_11898del |
|---|---|---|---|
Moderate evidence | PM2 – the prevalence of the variants in affected individuals is significantly increased compared with the prevalence in controls | 1) The variant was not found in 180 healthy Latvian control chromosomes 2) 0.00004119 (for Europeans in ExAC database) | 1) The variant was not found in 180 healthy Latvian control chromosomes 2) Not reporteda |
PM3 – for recessive disorders, detected in trans with a pathogenic allele | Located in trans position with other allele (in our case likely pathogenic allele) | Located in trans position with other allele (in our case likely pathogenic allele) | |
Supporting evidence | PP3 – multiple lines of computational evidence support a deleterious effect on the gene product | 1) HSF – predicted WT donor site broken ΔCT- -13.62%b (max entropy − 67.38%c) 2) Mutalyzer – variant located near to splice site 3) MutationTaster – disease causing (protein features (might be) affected; splice site change) | 1) HSF – predicted WT donor site broken ΔCT-55.3%b (max entropy − 284.9%c) 2) Mutalyzer - variant located in splice site 3) MutationTaster – disease causing (protein features (might be) affected; splice site change) |
PP4 – patient’s phenotype or family history is highly specific for disease with single genetic etiology | Yes | Yes | |
PP5 – reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation | Passuello et al., 2009 | None | |
Total score | Likely pathogenic | Likely pathogenic |