2-38071195-C-T

Position:

chr2-38071195-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong

The NM_000104.4(CYP1B1):c.1159G>A(p.Glu387Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000254 in 1,613,552 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00026 ( 0 hom. )

Consequence

CYP1B1
NM_000104.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15O:1

Conservation

PhyloP100: 7.80

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 16 ACMG points.

PM1

In a helix (size 13) in uniprot entity CP1B1_HUMAN there are 16 pathogenic changes around while only 1 benign (94%) in NM_000104.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.966

PP5

Variant 2-38071195-C-T is Pathogenic according to our data. Variant chr2-38071195-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 7735.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-38071195-C-T is described in Lovd as [Pathogenic]. Variant chr2-38071195-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.1159G>A	p.Glu387Lys	missense_variant	3/3	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.1159G>A	p.Glu387Lys	missense_variant	3/3	1	NM_000104.4	ENSP00000478561.1		Q16678

Frequencies

GnomAD3 genomes

AF:

0.000164

AC:

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000293

AC:

AN:

249210

Hom.:

AF XY:

0.000252

AC XY:

AN XY:

135136

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000492

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000490

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.000263

AC:

385

AN:

1461390

Hom.:

Cov.:

AF XY:

0.000274

AC XY:

199

AN XY:

727012

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.000492

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000378

Gnomad4 NFE exome

AF:

0.000309

Gnomad4 OTH exome

AF:

0.000232

GnomAD4 genome

AF:

0.000164

AC:

AN:

152162

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74318

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000243

Hom.:

Bravo

AF:

0.000246

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000466

AC:

ExAC

AF:

0.000329

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000178

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:15Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	May 27, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 12, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 02, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 05, 2021	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) -

Glaucoma 3A

Pathogenic:4Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Genomic Medicine Lab, University of California San Francisco	May 14, 2020	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2008	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -
Pathogenic, no assertion criteria provided	research	Institute of Medical Molecular Genetics, University of Zurich	Aug 01, 2019	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

Glaucoma 3A;C4310623:Anterior segment dysgenesis 6

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 02, 2024

- -

Anterior segment dysgenesis 6

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 21, 2024

- -

Primary congenital glaucoma

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Apr 09, 2021

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. -

CYP1B1-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 29, 2024

The CYP1B1 c.1159G>A variant is predicted to result in the amino acid substitution p.Glu387Lys. This variant has been reported many times in the homozygous and compound heterozygous states in individuals with congenital glaucoma (see for examples: Plásilová et al. 1999. PubMed ID: 10227395; Martin et al. 2000. PubMed ID: 10851252; Reis et al. 2016. PubMed ID: 27272408). This variant is reported in 0.048% of alleles in individuals of Latino 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/7735/). Given the evidence, we interpret this variant as pathogenic. -

Congenital glaucoma

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 25, 2024

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. -

Glaucoma of childhood

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 13, 2017

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 . -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Pathogenic

0.46

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.79

D;T;D

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.98

.;D;D

M_CAP

Pathogenic

0.40

MetaRNN

Pathogenic

0.97

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.4

H;.;H

PrimateAI

Uncertain

0.69

Sift4G

Pathogenic

0.0

D;D;D

Vest4

0.96

MVP

0.60

ClinPred

0.98

GERP RS

5.8

Varity_R

0.97

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