ClinVar

Description

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 469 of the CYP1B1 protein (p.Arg469Trp). This variant is present in population databases (rs28936701, gnomAD 0.007%). This missense change has been observed in individual(s) with primary congenital glaucoma (PMID: 9463332, 10655546, 18852424, 19234632, 25261878, 27508083, 32860008). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as 8242C>T. ClinVar contains an entry for this variant (Variation ID: 7733). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CYP1B1 protein function. Experimental studies have shown that this missense change affects CYP1B1 function (PMID: 19234632, 27243976). For these reasons, this variant has been classified as Pathogenic.