ClinVar

Description

The CYP1B1 c.1103G>A variant is predicted to result in the amino acid substitution p.Arg368His. This variant has been reported in the heterozygous and homozygous states in individuals with primary congenital glaucoma (Pasutto et al. 2010. PubMed ID: 19643970; Bejjani et al. 2000. PubMed ID: 10655546). A non-penetrant phenotype has been observed in a family homozygous for this variant (Bejjani et al. 2000. PubMed ID: 10655546). Additionally, digenic inheritance has been reported in an individual who was heterozygous for this variant and a pathogenic variant in the MYOC gene, which has also been associated with glaucoma (Vincent et al. 2002. PubMed ID: 11774072). Potential digenic inheritance has also been reported in two families who were heterozygous for the CYP1B1 c.1103G>A variant as well as a variant in the TEK gene, which has been associated with primary congenital glaucoma (Kabra et al. 2017. PubMed ID: 28620713). In functional studies, the p.Arg368His amino acid change resulted in substantially reduced estradiol and retinol metabolizing activity (Banerjee et al. 2016. PubMed ID: 27243976). Notably, other substitutions of the same amino acid (p.Arg368Cys and p.Arg368Leu) have been documented causative for glaucoma (HGMD - Human Gene Mutation Database). The CYP1B1 c.1103G>A variant has been registered in public databases with allele frequencies up to ~3%, including 13 homozygotes, which is likely too high to be consistent with highly penetrant pathogenic variant. This variant is also registered in the ClinVar database with conflicting interpretations of pathogenicity (https://www.ncbi.nlm.nih.gov/clinvar/variation/7739/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.