NM_001202543.1:c.2983C>T (p.Arg995Ter) is a nonsense variant in exon 19 of CUX1 predicted to undergo nonsense-mediated decay, meeting PVS1 at very strong strength.

The variant is absent from gnomAD v2.1 (0/251,110 alleles) and v4.1, meeting PM2 at supporting strength.

The variant has been classified as Pathogenic in ClinVar (Variation ID: 4532047) by a reputable clinical diagnostic laboratory (Victorian Clinical Genetics Services), meeting PP5 at supporting strength.

Under ACMG/AMP 2015 combination rules, one Very Strong criterion (PVS1) plus two Supporting criteria (PM2, PP5) is sufficient for a Pathogenic classification.

Heterozygous loss-of-function variants in CUX1 cause an autosomal dominant neurodevelopmental disorder characterized by global developmental delay, intellectual disability, hypotonia, and seizures, as established by Oppermann et al. (2023) in a cohort of 34 individuals.

No benign evidence was identified: the variant is too rare for BA1/BS1, no functional studies demonstrate a benign effect, and no lack of segregation or alternate molecular basis has been reported.

Final classification: Pathogenic. PVS1_VeryStrong + PM2_Supporting + PP5_Supporting.