2-38075207-C-T

Position:

chr2-38075207-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PP3_ModeratePP5_Very_Strong

The NM_000104.4(CYP1B1):c.182G>A(p.Gly61Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000308 in 1,579,668 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00032 ( 2 hom. )

Consequence

CYP1B1
NM_000104.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:17U:1O:1

Conservation

PhyloP100: 7.71

Variant links:

Genes affected

CYP1B1 (HGNC:2597): (cytochrome P450 family 1 subfamily B member 1) This gene encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. The enzyme encoded by this gene localizes to the endoplasmic reticulum and metabolizes procarcinogens such as polycyclic aromatic hydrocarbons and 17beta-estradiol. Mutations in this gene have been associated with primary congenital glaucoma; therefore it is thought that the enzyme also metabolizes a signaling molecule involved in eye development, possibly a steroid. [provided by RefSeq, Jul 2008]

CYP1B1 links:

CYP1B1 (HGNC:):

CYP1B1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.916

PP5

Variant 2-38075207-C-T is Pathogenic according to our data. Variant chr2-38075207-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 7730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-38075207-C-T is described in Lovd as [Pathogenic]. Variant chr2-38075207-C-T is described in Lovd as [Pathogenic]. Variant chr2-38075207-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP1B1	NM_000104.4 linkuse as main transcript	c.182G>A	p.Gly61Glu	missense_variant	2/3	ENST00000610745.5	NP_000095.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP1B1	ENST00000610745.5 linkuse as main transcript	c.182G>A	p.Gly61Glu	missense_variant	2/3	1	NM_000104.4	ENSP00000478561.1		Q16678

Frequencies

GnomAD3 genomes

AF:

0.000217

AC:

AN:

152256

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.000309

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.000318

AC:

AN:

198162

Hom.:

AF XY:

0.000386

AC XY:

AN XY:

108850

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000167

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000362

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000449

Gnomad OTH exome

AF:

0.00156

GnomAD4 exome

AF:

0.000317

AC:

453

AN:

1427294

Hom.:

Cov.:

AF XY:

0.000345

AC XY:

244

AN XY:

707904

show subpopulations

Gnomad4 AFR exome

AF:

0.000181

Gnomad4 AMR exome

AF:

0.000171

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000310

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000326

Gnomad4 OTH exome

AF:

0.000438

GnomAD4 genome

AF:

0.000217

AC:

AN:

152374

Hom.:

Cov.:

AF XY:

0.000201

AC XY:

AN XY:

74512

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000309

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.000641

Hom.:

Bravo

AF:

0.000340

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000120

AC:

ExAC

AF:

0.000339

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:17Uncertain:1Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Glaucoma 3A

Pathogenic:7Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 17, 2024	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 2002	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jun 24, 2022	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 -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	Aug 25, 2019	- -
Pathogenic, no assertion criteria provided	curation	Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University	Jun 12, 2024	- -

not provided

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Feb 01, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 28, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2022	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) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2022	- -

Anterior segment dysgenesis 6

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 2002	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 26, 2024	- -

Glaucoma 3, primary infantile, B;C1856439:Glaucoma 3A;C4310623:Anterior segment dysgenesis 6

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 24, 2022

- -

Primary congenital glaucoma

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jul 31, 2024

Variant summary: CYP1B1 c.182G>A (p.Gly61Glu) 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 0.00032 in 198162 control chromosomes in the gnomAD database, including 2 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in CYP1B1 causing Primary Congenital Glaucoma (0.00032 vs 0.0043), allowing no conclusion about variant significance. c.182G>A has been reported in the literature in multiple individuals affected with Primary Congenital Glaucoma (Bejjani_1998). These data indicate that the variant is very likely to be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 9463332). ClinVar contains an entry for this variant (Variation ID: 7730). Based on the evidence outlined above, the variant was classified as pathogenic. -

CYP1B1-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 09, 2024

The CYP1B1 c.182G>A variant is predicted to result in the amino acid substitution p.Gly61Glu. This variant in compound heterozygous and homozygous states has been reported to be causative for primary congenital glaucoma (PCG) (Bejjani et al. 1998. PubMed ID: 9463332; Abu-Amero et al. 2015. PubMed ID: 24099281; Micheal et al. 2015. PubMed ID: 25091052; Stoilov et al. 1998. PubMed ID: 9497261). This variant was seen in 78% of the PCG chromosomes analyzed and reported as a common variant in the Saudi Arabian population (Bejjani et al. 1998. PubMed ID: 9463332, reported as 3987G>A change). Functional studies have shown that this variant significantly reduces enzyme activity (Banerjee et al. 2016. PubMed ID: 27243976). This variant is reported in 0.041% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

Congenital glaucoma

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

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. -

Glaucoma 3A;C4310623:Anterior segment dysgenesis 6

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Coban-Akdemir Lab, University of Texas Health Science Center

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Pathogenic

0.43

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.76

D;D;.

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.94

.;D;D

M_CAP

Pathogenic

0.89

MetaRNN

Pathogenic

0.92

D;D;D

MetaSVM

Pathogenic

0.89

MutationAssessor

Pathogenic

4.0

H;H;.

PrimateAI

Pathogenic

0.87

Sift4G

Pathogenic

0.0

D;D;.

Vest4

0.94

MVP

0.58

ClinPred

0.96

GERP RS

3.4

Varity_R

0.80

gMVP

0.99

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over