Table 1.

Categories of prenatal variants of uncertain significance

Category and rationale	Specific phenotype	Data available regarding likelihood of an affected fetus
CNVs with OMIM morbid genes	Variable	Variable
CNVs that are found in known disease-causing genes, but the particular variant has never been reported before
Likely carrier	Yes	Yes
In cases of autosomal recessive disorders, a deletion or duplication may be found on one allele. It is unknown whether there is a sequencing error on the other allele until sequencing testing is performed
Incomplete penetrance	Yes	Yes
Patients with a pathogenic variant may not express the phenotype at all, or may do so only after a certain age
Large ROH	Variable	Yes
ROHs can occur in the setting of ancestral relatedness, consanguinity or UPD. If there are two copies of pathogenic variants with sequencing errors in a disease associated with autosomal recessive inheritance, or if UPD occurs in a chromosome with imprinted genes, there may be an affected fetus. Our institution defines large ROHs as >10 Mb in interstitial regions or >3 Mb in terminal regions in chromosomes with imprinted genes, or ROHs constituting >3.5% of the genome
Large size	No	Yes
Deletions or duplications >1 Mb without any OMIM morbid genes
Mosaicism	Yes	Yes
Patients with mosaic CNVs tend to have a less severe phenotype than those without mosaicism

CNV, copy number variant; ROH, region of homozygosity; UPD, uniparental disomy.