Submissions for variant NM_000104.4(CYP1B1):c.1159G>A (p.Glu387Lys)

gnomAD frequency: 0.00018  dbSNP: rs55989760

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000724653	SCV000331834	pathogenic	not provided	2018-08-02	criteria provided, single submitter	clinical testing
Invitae	RCV001201386	SCV000626998	pathogenic	Congenital glaucoma	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 387 of the CYP1B1 protein (p.Glu387Lys). This variant is present in population databases (rs55989760, gnomAD 0.05%). This missense change has been observed in individual(s) with primary congenital glaucoma (PCG) (PMID: 9497261, 10227395, 15342693, 18414103, 21081970, 21600657, 23218183, 25109919, 27272408, 27820421). It is commonly reported in individuals of Slovak ancestry (PMID: 9497261, 10227395, 15342693, 18414103, 21081970, 21600657, 23218183, 25109919, 27272408, 27820421). ClinVar contains an entry for this variant (Variation ID: 7735). 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) performed at Invitae indicates that this missense variant is expected to disrupt CYP1B1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects CYP1B1 function (PMID: 18227148, 23218183, 27243976). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000791358	SCV000712165	pathogenic	Glaucoma of childhood	2017-05-13	criteria provided, single submitter	clinical testing	The p.Glu387Lys variant in CYP1B1 is a well-established pathogenic variant for p rimary congenital glaucoma, and represents a founder variant in the Slovak Roman i population (Azmanov 2011, Kelbermann 2011, Li 2011, Lim 2013, Plasilova 1999, Reis 2016, Sivadorai 2008). In vitro functional studies support that the p.Glu38 7Lys variant impacts protein function (Banjeree 2016 and Lopez-Garrido 2013). Th is variant has also been identified in 36/64286 European chromosomes by the Exom e Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs55989760 ); however, this frequency is low enough to be consistent with a recessive carri er frequency. In summary, the p.Glu387Lys variant meets criteria to be classifie d as pathogenic for primary congenital glaucoma in an autosomal recessive manner .
Baylor Genetics	RCV000008174	SCV001162948	pathogenic	Glaucoma 3A		criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001375550	SCV001572419	pathogenic	Primary congenital glaucoma	2021-04-09	criteria provided, single submitter	clinical testing	Variant summary: CYP1B1 c.1159G>A (p.Glu387Lys) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00036 in 249726 control chromosomes (gnomAD and publication data). This frequency is not higher than expected for a pathogenic variant in CYP1B1 causing Primary Congenital Glaucoma (0.00036 vs 0.0043), allowing no conclusion about variant significance. c.1159G>A has been reported in the literature in multiple individuals affected with Primary Congenital Glaucoma and Primary open-angle glaucoma. Moreover, the variant was shown to co-segregate with disease in several different families (Stoilov_1998, Plasilova_1999, Lopez-Garrido_2012, Melki_2004). These data indicate that the variant is very likely to be associated with disease. In addition, this variant has been reported as a founder variant in Slovak Gypsies (Roms) (Plasilova_1999). Functional studies report this variant results in having significantly reduced enzyme activity (Lopez-Garrido_2012, Banerjee_2016). Five ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Genomic Medicine Lab, University of California San Francisco	RCV000008174	SCV001572946	likely pathogenic	Glaucoma 3A	2020-05-14	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000724653	SCV001747947	pathogenic	not provided	2021-06-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000724653	SCV002512881	pathogenic	not provided	2021-08-05	criteria provided, single submitter	clinical testing	Recognized as founder variant in the Slovak Roman population (Plasilova et al., 1999); Published functional studies demonstrate a damaging effect whereby enzymatic activity was evaluated in transiently transfected HEK-293T cells. The mutant protein was completely inactive. The levels of mutant CYP1B1 were slightly lower than wild-type, indicating reduced stability. (Lopez-Garrido et al., 2013); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 19204079, 25109919, 10227395, 9497261, 27243976, 27820421, 27272408, 28448622, 16735994, 23218701, 21854771, 21600657, 31453292, 31980526, 32832252, 31589614, 10851252, 23218183)
Fulgent Genetics, Fulgent Genetics	RCV002490338	SCV002784513	pathogenic	Glaucoma 3A; Glaucoma 3, primary infantile, B; Anterior segment dysgenesis 6	2021-12-27	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000724653	SCV003819395	pathogenic	not provided	2022-08-12	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003466834	SCV004215450	pathogenic	Anterior segment dysgenesis 6	2023-10-28	criteria provided, single submitter	clinical testing
OMIM	RCV000008174	SCV000028379	pathogenic	Glaucoma 3A	2008-07-01	no assertion criteria provided	literature only
Institute of Medical Molecular Genetics, University of Zurich	RCV000008174	SCV001424838	pathogenic	Glaucoma 3A	2019-08-01	no assertion criteria provided	research
GeneReviews	RCV000008174	SCV002106341	not provided	Glaucoma 3A		no assertion provided	literature only