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Variant classification – likely pathogenic — RACP Paediatrics MCQ

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ModerateGeneticsVariant classification – likely pathogenicRACP Paediatrics

Whole exome sequencing in a child with developmental delay identifies a variant in a known disease gene that has never been reported before. In-silico prediction tools are conflicting. Parental testing shows it is de novo. How should this variant be classified per ACMG guidelines?

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Correct answer: D — Likely pathogenic – actionable

A de novo variant (strong evidence for pathogenicity per ACMG PS2 criterion) in a known disease gene relevant to the patient's phenotype, even if novel, is typically classified as 'likely pathogenic' when combined with computational evidence. ACMG guidelines use a 5-tier classification: pathogenic, likely pathogenic, VUS, likely benign, benign. Likely pathogenic variants are considered actionable for clinical decision-making.

Reference: RACP Paediatric Curriculum – Genetics; ACMG/AMP – 2015 – Variant Classification Guidelines