2-38074404-C-T

Position:

chr2-38074404-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PM5PP3_ModeratePP5_Very_Strong

The ENST00000610745.5(CYP1B1):c.985G>A(p.Gly329Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000958 in 1,461,098 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G329D) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

CYP1B1
ENST00000610745.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 5.62

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-AS1 (HGNC:28543): (CYP1B1 antisense RNA 1)

CYP1B1-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr2-38074403-C-T is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.921

PP5

Variant 2-38074404-C-T is Pathogenic according to our data. Variant chr2-38074404-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 632362.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP1B1	NM_000104.4 linkuse as main transcript	c.985G>A	p.Gly329Ser	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.985G>A	p.Gly329Ser	missense_variant	2/3	1	NM_000104.4	ENSP00000478561	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000121

AC:

AN:

248888

Hom.:

AF XY:

0.0000222

AC XY:

AN XY:

135124

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000546

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000178

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000958

AC:

AN:

1461098

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

726850

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000630

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Anterior segment dysgenesis 6

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 19, 2024

- -

Glaucoma 3A

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Nov 21, 2018

The CYP1B1 c.985G>A (p.Gly329Ser) missense variant has been reported in one study and found in three individuals with primary congenital glaucoma including one each in a homozygous state, compound heterozygous state with a frameshift variant and heterozygous state (Kim et al. 2011). The variant was absent from 400 control chromosomes and is reported at a frequency of 0.000016 in the Total population of the Genome Aggregation Database. HEK293T cells expressing the p.Gly329Ser variant completely lacked retinol metabolizing activity (Banerjee et al. 2016). Based on the evidence, the p.Gly329Ser variant is classified as likely pathogenic for primary congenital glaucoma. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Primary congenital glaucoma

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Mar 23, 2022

Variant summary: CYP1B1 c.985G>A (p.Gly329Ser) results in a non-conservative amino acid change located in the conserved helixe I (aa316-349, Jeannot_2007) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 249004 control chromosomes (gnomAD and publication data). c.985G>A has been reported in the literature in individuals affected with Primary Congenital Glaucoma, including one homozygote (Kim_2011, Suh_2012). These data indicate that the variant may be associated with disease. Functional studies report experimental evidence evaluating an impact on protein function, where the variant protein was found to be enzymatically null for both estradiol and retinoic acid metabolism (Jeannot_2007, Banerjee_2016). In addition, other missense variants in the same residue (G329D and G329V) have been reported in the Human Gene Mutation Database in association with Primary Congenital Glaucoma (PMID: 17718864, 17893647), supporting the functional importance of this residue of the protein. Two ClinVar submitters have assessed the variant since 2014: one classified the variant as likely pathogenic, and one as of uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Congenital glaucoma

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 30, 2023

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 329 of the CYP1B1 protein (p.Gly329Ser). This variant is present in population databases (rs777678299, gnomAD 0.01%). This missense change has been observed in individuals with primary congenital glaucoma (PMID: 22942166). ClinVar contains an entry for this variant (Variation ID: 632362). 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 not expected to disrupt CYP1B1 protein function. Experimental studies have shown that this missense change affects CYP1B1 function (PMID: 17363580, 27243976). This variant disrupts the p.Gly329 amino acid residue in CYP1B1. Other variant(s) that disrupt this residue have been observed in individuals with CYP1B1-related conditions (PMID: 31024815), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.66

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Pathogenic

0.33

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.57

D;D

Eigen

Uncertain

0.66

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.95

.;D

M_CAP

Pathogenic

0.59

MetaRNN

Pathogenic

0.92

D;D

MetaSVM

Uncertain

-0.19

MutationAssessor

Benign

1.9

L;L

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.77

Sift4G

Benign

0.069

T;T

Vest4

0.94

MVP

0.44

ClinPred

0.94

GERP RS

4.0

Varity_R

0.87

gMVP

0.78

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