Submissions for variant NM_000104.4(CYP1B1):c.1405C>T (p.Arg469Trp)

gnomAD frequency: 0.00004  dbSNP: rs28936701

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000255845	SCV000321540	pathogenic	not provided	2023-06-12	criteria provided, single submitter	clinical testing	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)
Centogene AG - the Rare Disease Company	RCV000008172	SCV001426595	pathogenic	Glaucoma 3A		criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000008172	SCV001440970	pathogenic	Glaucoma 3A	2019-01-01	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000255845	SCV002018099	pathogenic	not provided	2020-04-25	criteria provided, single submitter	clinical testing
3billion	RCV000008172	SCV002058739	pathogenic	Glaucoma 3A	2022-01-03	criteria provided, single submitter	clinical testing	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002512894	SCV003299556	pathogenic	Congenital glaucoma	2024-01-26	criteria provided, single submitter	clinical testing	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003155021	SCV003844825	pathogenic	Primary congenital glaucoma	2023-02-03	criteria provided, single submitter	clinical testing	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.
Baylor Genetics	RCV003466833	SCV004215465	pathogenic	Anterior segment dysgenesis 6	2024-02-17	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000008172	SCV004804685	pathogenic	Glaucoma 3A	2024-03-17	criteria provided, single submitter	research
OMIM	RCV000008172	SCV000028377	pathogenic	Glaucoma 3A	1998-02-01	no assertion criteria provided	literature only
Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS)	RCV000008172	SCV003927823	pathogenic	Glaucoma 3A	2023-04-01	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004732535	SCV005350334	pathogenic	CYP1B1-related disorder	2024-07-29	no assertion criteria provided	clinical testing	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.