rs148542782

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The ENST00000610745.5(CYP1B1):​c.1168C>T​(p.Arg390Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000397 in 1,613,650 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R390H) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000038 ( 0 hom. )

Consequence

CYP1B1
ENST00000610745.5 missense

Scores

12
3
1

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 6.74
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PM1
In a helix (size 13) in uniprot entity CP1B1_HUMAN there are 23 pathogenic changes around while only 1 benign (96%) in ENST00000610745.5
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr2-38071185-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 592512.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.967
PP5
Variant 2-38071186-G-A is Pathogenic according to our data. Variant chr2-38071186-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 335952.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-38071186-G-A is described in Lovd as [Pathogenic]. Variant chr2-38071186-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CYP1B1NM_000104.4 linkuse as main transcriptc.1168C>T p.Arg390Cys missense_variant 3/3 ENST00000610745.5 NP_000095.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CYP1B1ENST00000610745.5 linkuse as main transcriptc.1168C>T p.Arg390Cys missense_variant 3/31 NM_000104.4 ENSP00000478561 P1

Frequencies

GnomAD3 genomes
AF:
0.0000591
AC:
9
AN:
152178
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.000103
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000240
AC:
6
AN:
249632
Hom.:
0
AF XY:
0.00000739
AC XY:
1
AN XY:
135272
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000267
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000376
AC:
55
AN:
1461472
Hom.:
0
Cov.:
35
AF XY:
0.0000358
AC XY:
26
AN XY:
727048
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000504
Gnomad4 SAS exome
AF:
0.0000232
Gnomad4 FIN exome
AF:
0.0000189
Gnomad4 NFE exome
AF:
0.0000414
Gnomad4 OTH exome
AF:
0.0000662
GnomAD4 genome
AF:
0.0000591
AC:
9
AN:
152178
Hom.:
0
Cov.:
32
AF XY:
0.0000134
AC XY:
1
AN XY:
74354
show subpopulations
Gnomad4 AFR
AF:
0.0000483
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000103
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000788
Hom.:
0
Bravo
AF:
0.0000416
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.0000247
AC:
3
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Anterior segment dysgenesis 6 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsFeb 19, 2024- -
Glaucoma 3A Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017The CYP1B1 c.1168C>T (p.Arg390Cys) variant is reported in a total of 12 individuals with primary congenital glaucoma (PCG), including eight homozygotes, three compound heterozygotes, and one heterozygote (Curry et al. 2004; Panicker et al. 2004; Sivadorai et al. 2008; Azmanov et al. 2010). A review by Li et al. (2011) noted the variant in 23 of 542 individuals with PCG, though zygosity is not described. The p.Arg390Cys variant was identified in the above studies in a heterozygous state in one of 715 control individuals and it is reported at a frequency of 0.00003 in the Total population of the Exome Aggregation Consortium. Based on the evidence, the p.Arg390Cys variant is classified as 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
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpApr 08, 2022Variant summary: CYP1B1 c.1168C>T (p.Arg390Cys) 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 2.4e-05 in 249632 control chromosomes. c.1168C>T has been reported in the literature as homozygous and compound heterozygous genotypes in multiple individuals affected with Primary Congenital Glaucoma (example, Reddy_2003, Lim_2013, Jackson_2020). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function was ascertained. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (Pathogenic, n=2). Based on the evidence outlined above, the variant was classified as pathogenic. -
not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingRevvity Omics, RevvityJun 22, 2021- -
Congenital glaucoma Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 20, 2023This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 390 of the CYP1B1 protein (p.Arg390Cys). This variant is present in population databases (rs148542782, gnomAD 0.006%). This missense change has been observed in individual(s) with primary congenital glaucoma (PMID: 15037581, 15255109). ClinVar contains an entry for this variant (Variation ID: 335952). 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%. This variant disrupts the p.Arg390 amino acid residue in CYP1B1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19536304, 27508083, 30108387). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.81
BayesDel_addAF
Pathogenic
0.35
D
BayesDel_noAF
Pathogenic
0.44
CADD
Pathogenic
27
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.81
D;T;D
Eigen
Pathogenic
0.96
Eigen_PC
Pathogenic
0.85
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Pathogenic
0.97
.;D;D
M_CAP
Uncertain
0.20
D
MetaRNN
Pathogenic
0.97
D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
4.3
H;.;H
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.65
T
Sift4G
Pathogenic
0.0
D;D;D
Vest4
0.89
MVP
0.60
ClinPred
0.99
D
GERP RS
5.0
Varity_R
0.92
gMVP
0.98

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.

Other links and lift over

dbSNP: rs148542782; hg19: chr2-38298329; API