Submissions for variant NM_000104.4(CYP1B1):c.182G>A (p.Gly61Glu)

gnomAD frequency: 0.00017  dbSNP: rs28936700

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000255452	SCV000321539	pathogenic	not provided	2022-03-03	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect, specifically, the variant causes reduced enzyme activity and decreased protein stability (Chavarria-Soley et al., 2008; Lopez-Garrido et al., 2010); Known as a Middle Eastern founder mutation (Li et al., 2011); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 32153331, 33745036, 26982174, 27243976, 9463332, 9497261, 31024815, 21854771, 25091052, 19793111, 24591815, 19204079, 18470941, 19643970, 24210336, 21596299, 19234632, 12372064, 26164761, 24099281, 23363883, 25261878, 28448622, 16862072, 30127590, 30207287, 30270463, 31980526, 34426522, 31589614, 15621878, 15037581, 33170892)
Fulgent Genetics, Fulgent Genetics	RCV000763083	SCV000893609	pathogenic	Glaucoma 3A; Glaucoma 3, primary infantile, B; Anterior segment dysgenesis 6	2022-03-24	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000008169	SCV001162951	pathogenic	Glaucoma 3A		criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000255452	SCV001247370	pathogenic	not provided	2022-02-01	criteria provided, single submitter	clinical testing
Invitae	RCV001206715	SCV001378037	pathogenic	Congenital glaucoma	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 61 of the CYP1B1 protein (p.Gly61Glu). This variant is present in population databases (rs28936700, gnomAD 0.04%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individuals with primary congenital glaucoma (PMID: 9463332, 12372064, 19234632). It is commonly reported in individuals of Saudi and Moroccan ancestry (PMID: 9463332, 12372064, 19234632). This variant is also known as c.3987G>A. ClinVar contains an entry for this variant (Variation ID: 7730). 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 80%. Experimental studies have shown that this missense change affects CYP1B1 function (PMID: 18470941, 19793111, 27243976). For these reasons, this variant has been classified as Pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000255452	SCV001480127	pathogenic	not provided	2021-02-01	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001335112	SCV001528169	pathogenic	Anterior segment dysgenesis 6	2018-12-28	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Genome-Nilou Lab	RCV000008169	SCV001623487	pathogenic	Glaucoma 3A	2021-05-18	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000255452	SCV002018104	pathogenic	not provided	2023-02-28	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000008169	SCV002557822	pathogenic	Glaucoma 3A	2022-06-24	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with congenital, juvenile, or adult onset primary open anglet glaucoma 3A (MIM#231300) and anterior segment dysgenesis 6, multiple subtypes (MIM#617315). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0112 - The condition associated with this gene has incomplete penetrance (PMID: 26550445, 19744731). (I) 0115 - Variants in this gene are known to have variable expressivity. Individuals with the same variants have been reported with variable severity and age of onset (PMID: 19744731). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to glutamic acid. (I) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (63 heterozygotes, 2 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated p450 domain (DECIPHER). (I) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. The p.(Gly61Arg) variant has been classified as pathogenic by a clinical laboratory in ClinVar. (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been observed in homozygous or compound heterozygous state in many individuals with primary congenital glaucoma, and has been described as hypomorphic due to its residual enzyme activity and reduced penentrance (ClinVar, DECIPHER, PMIDs: 19234632, 19744731). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. This variant has been shown to have 25% of wild type activity and significantly reduced protein expression using fluorimetric and western blot assays on transfected HEK-293T cells (PMID: 19234632). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000008169	SCV004847100	pathogenic	Glaucoma 3A	2024-03-17	criteria provided, single submitter	clinical testing
OMIM	RCV000008169	SCV000028374	pathogenic	Glaucoma 3A	2002-10-01	no assertion criteria provided	literature only
Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University	RCV000008169	SCV000891494	uncertain significance	Glaucoma 3A	2017-12-30	no assertion criteria provided	curation
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	RCV000008169	SCV001132972	pathogenic	Glaucoma 3A	2019-08-25	no assertion criteria provided	clinical testing
OMIM	RCV001335112	SCV001652917	pathogenic	Anterior segment dysgenesis 6	2002-10-01	no assertion criteria provided	literature only
GeneReviews	RCV000008169	SCV002106340	not provided	Glaucoma 3A		no assertion provided	literature only
Coban-Akdemir Lab, University of Texas Health Science Center	RCV003483427	SCV004231748	uncertain significance	Glaucoma 3A; Anterior segment dysgenesis 6		no assertion criteria provided	clinical testing	The affected individual was severely delayed with no communication skills and died at a young age. Since the subject was deceased, we could not perform an ophthalmologic evaluation.