Fig. 1: For rare nontruncating variants in autosomal dominant disease, evidence classes and American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) rules (rule codes from Richards et al.3) can be broadly grouped by their power to distinguish between pathogenic and benign variants (y-axis) and the likelihood that such evidence will be available (x-axis). | Genetics in Medicine

Fig. 1: For rare nontruncating variants in autosomal dominant disease, evidence classes and American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) rules (rule codes from Richards et al.3) can be broadly grouped by their power to distinguish between pathogenic and benign variants (y-axis) and the likelihood that such evidence will be available (x-axis).

From: Enhancing rare variant interpretation in inherited arrhythmias through quantitative analysis of consortium disease cohorts and population controls

Fig. 1

Variant-specific evidence (such as cosegregation in family pedigrees) is powerful but often unavailable for genetically heterogeneous diseases. Supporting evidence (such as population frequency) can be applied to most variants but is rarely sufficient for definitive classification. If available, data from case–control studies, relating to enrichment of specific variants or classes of variants, provide powerful gene/disease-specific evidence and help to address the high false negative rate associated with stringent contemporary guidelines.

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