ClinVar Genomic variation as it relates to human health

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.

Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000007733, PMID:9463332, PS1_S). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 9463332, PM3_M). It was co-segregated with Glaucoma 3A, primary open angle, congenital, juvenile, or adult onset in multiple affected family members (PMID: 9463332, PP1_P). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.723, PP3_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000048, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

Variant summary: CYP1B1 c.1405C>T (p.Arg469Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-05 in 251470 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in CYP1B1 causing Primary Congenital Glaucoma (4.8e-05 vs 0.0043), allowing no conclusion about variant significance. c.1405C>T has been reported in the literature as a homozygous and compound heterozygous genotype in multiple individuals affected with Primary Congenital Glaucoma (Campos-Mollo_2009, Chitsazian_2007 etc.) . These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Campos-Mollo_2009). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31589614, 32860008, 19204079, 9463332, 14729846, 9497261, 17893647, 27243976, 27508083, 28384041, 27777502, 25261878, 34426522, 17591938, 36518267, 35407656, 36083974, 35085548, 36995002, 10655546, 18852424, 19234632, 37107695, 11740343)

The CYP1B1 c.1405C>T variant is predicted to result in the amino acid substitution p.Arg469Trp. This variant has been reported in the homozygous and compound heterozygous states in individuals with congenital glaucoma (Bejjani et al. 1998. PubMed ID: 9463332; Banerjee et al. 2016. PubMed ID: 27243976; Rauf et al. 2016. PubMed ID: 27508083; Reis et al. 2016. PubMed ID: 27777502). This variant is reported in 0.0070% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant has been classified as pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/7733/). Given the evidence, we interpret this variant as pathogenic.