PVS1
Germline loss of function is an established disease mechanism for CUX1, but this duplication does not fall into the generic PVS1 default null-variant categories of nonsense, frameshift, or canonical +/-1,2 splice variants, so PVS1 is not applied.
PS1
No evidence was identified showing that this variant results in the same amino acid change as a previously established pathogenic variant.
PS2
No confirmed de novo occurrence data were identified for this variant.
PS3
No well-established functional studies were identified for this variant.
PS4
No evidence was identified showing that this variant is enriched in affected individuals compared with controls.
PM1
Available evidence does not establish that this variant lies in a mutational hotspot or a well-studied critical region without benign variation.
PM3
No data were identified showing this variant in trans with another pathogenic variant.
PM4
This duplication extends from coding sequence into intronic sequence, and the resulting protein consequence remains uncertain, so protein-length change evidence cannot be applied from the available data.
PM5
No evidence was identified for a different pathogenic missense change at the same residue because the protein consequence of this variant is unresolved.
PM6
No presumed de novo occurrence data were identified for this variant.
PP1
No segregation data were identified for this variant.
PP3
Available computational evidence does not support a damaging splicing effect because SpliceAI shows a maximum delta score of 0.05, which is below commonly used splice-impact thresholds; REVEL and BayesDel were not available because this is not an SNV.
PP4
No phenotype information was provided to determine whether the observed clinical features are highly specific for a CUX1-related disorder.
PP5
No reputable source classification was identified for this variant.
