Clinical Genetic Testing Report

Example Genetics Laboratory (teaching example)

Test: Whole Exome Sequencing

Strategy: Trio (proband + both parents)

PATIENT

3-year-old female — GDD, drug-resistant epilepsy (onset 4 mo), mild cerebral atrophy on MRI

Gene	Variant (HGVS)	Zygosity	Inheritance	Classification
STXBP1	c.1631C>T (p.Pro544Leu)	Heterozygous	De novo	VUS

ACMG Criteria Walkthrough

Criterion	Evidence	Strength	Points
PS2	Confirmed de novo (absent from both parents by trio WES)	Strong	+4
PM2_Supporting	Absent from gnomAD (321,000 individuals)	Supporting	+1
PP3	REVEL 0.48 (below ClinGen 0.644 threshold) — does not meet PP3	—	0
PS3	No published functional studies for this specific variant	—	—
Total Score			5 pts → VUS (1 point short of LP)

Key lesson: de novo alone is not enough

Even with confirmed de novo status (+4) and population rarity (+1), this variant scores only 5 points — one short of LP. The computational evidence didn’t cross the threshold. This variant could be upgraded over time if: (1) functional studies demonstrate disrupted STXBP1 function, (2) additional unrelated patients are found with the same de novo variant, or (3) gene-specific VCEP guidelines provide more nuanced criteria.

A 2-year-old with developmental delay has exome sequencing that identifies a variant classified as VUS (Variant of Uncertain Significance) in a gene associated with intellectual disability. The parents ask whether this confirms their child's diagnosis. Which response is most appropriate?