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Variant Interpretation & ACMG Classification
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Question 1
A heterozygous frameshift variant is identified in a child with a neurogenetic condition. Under ACMG/AMP guidelines, applying PVS1 (null variant) at full strength requires verification of which critical gene-level property?
A
The gene must have a gnomAD allele frequency below 0.01% for all LoF variants
B
Loss of function must be the established disease mechanism for the gene (not gain-of-function)
C
The variant must be absent from ClinVar and all published literature
D
The gene must be located in a ClinGen-curated region with established triplosensitivity
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