rs56010818

chr2-38071185-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000104.4(CYP1B1):c.1169G>A(p.Arg390His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000397 in 1,613,616 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. R390C) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000037 (0 hom.)
• Consequence: CYP1B1 NM_000104.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 7.80

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a helix (size 13) in uniprot entity CP1B1_HUMAN there are 21 pathogenic changes around while only 1 benign (95%) in NM_000104.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-38071186-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 2203048.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.939
• PP5: Variant 2-38071185-C-T is Pathogenic according to our data. 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. Variant chr2-38071185-C-T is described in Lovd as [Pathogenic]. Variant chr2-38071185-C-T is described in Lovd as [Likely_pathogenic]. Variant chr2-38071185-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP1B1	NM_000104.4	c.1169G>A	p.Arg390His	missense_variant	3/3	ENST00000610745.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP1B1	ENST00000610745.5	c.1169G>A	p.Arg390His	missense_variant	3/3	1	NM_000104.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152120 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000921 AC: 23 AN: 249616 Hom.: 0 AF XY: 0.000111 AC XY: 15 AN XY: 135260

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000997

Gnomad EAS exome AF: 0.000599

Gnomad SAS exome AF: 0.000294

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000178

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000369 AC: 54 AN: 1461496 Hom.: 0 Cov.: 35 AF XY: 0.0000413 AC XY: 30 AN XY: 727062

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.000278

Gnomad4 FIN exome AF: 0.0000189

Gnomad4 NFE exome AF: 0.0000180

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152120 Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5 AN XY: 74314

Gnomad4 AFR AF: 0.0000966

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000578

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000276 Hom.: 0

Bravo AF: 0.0000491

ExAC AF: 0.000148 AC: 18

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Anterior segment dysgenesis 6 Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 18, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Sep 02, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Pediatrics Genetics, Post Graduate Institute of Medical Education and Research	Aug 31, 2023	This variant is not present in gnomad. PM1+PM2+PP3+PP5 -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	Nov 16, 2023	A homozygous missense variant in exon 3 of the CYP1B1 gene that results in the amino acid substitution of Histidine for Arginine at codon 390 (p.Arg390His) was detected. The observed variant has previously been reported in patients affected with congenital glaucoma [PMID: 9497261]. This variant has not been reported in the 1000 genomes databases and has a minor allele frequency of 0.006%, 0.009% and 0.004% in the gnomAD (v3.1), gnomdAD (v2.1) and topmed databases respectively. The in-silico prediction of the variant are probably damaging by PolyPhen-2 (HumDiv), damaging by SIFT and LRT. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as likely pathogenic. -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 26, 2022	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 30820150, 25527694, 27508083, 19536304, 31236345, 29903728, 22878448, 19204079, 30108387, 30270463, 29540704, 34019190, 32830442, 19247456, 9497261, 25018621, 15475877) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 03, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	May 03, 2020	- -

Glaucoma 3A Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

-

The missense c.1169G>A p.Arg390His variant in CYP1B1 gene has been reported in homozygous and compound heterozygous states in multiple individuals affected as one of the most frequent variant causing primary congenital glaucoma Rauf et al. 2016; Song et al. 2019. This variant is reported to be segregating with the disease in the related individuals Bashir et al. 2018. This variant is reported with an allele frequency of 0.01% in the gnomAD exomes database and is novel not in any individuals in 1000 Genomes database. This variant has been reported to the ClinVar database as Likely Pathogenic / Pathogenic multiple submissions. The amino acid change p.Arg390His in CYP1B1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Arg at position 390 is changed to a His changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic. -

Primary congenital glaucoma Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Jan 29, 2024

Variant summary: CYP1B1 c.1169G>A (p.Arg390His) 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 9.2e-05 in 249616 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in CYP1B1 causing Primary Congenital Glaucoma (9.2e-05 vs 0.0043), allowing no conclusion about variant significance. c.1169G>A has been reported in the literature as a biallelic genotype in many individuals affected with Primary Congenital Glaucoma and has been found to segregate with disease in multiple families (e.g. Sheikh_2014, Chitsazian_2007). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 17591938, 25018621). ClinVar contains an entry for this variant (Variation ID: 592512). Based on the evidence outlined above, the variant was classified as pathogenic. -

Congenital glaucoma Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 390 of the CYP1B1 protein (p.Arg390His). This variant is present in population databases (rs56010818, gnomAD 0.06%). This missense change has been observed in individual(s) with primary congenital glaucoma (PMID: 19536304, 27508083, 30108387). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 592512). 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: 15037581, 20664688; Invitae). 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	0.82
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Pathogenic	0.46
Cadd	Pathogenic	32
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	D
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.94	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.3	H;.;H
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.60	T
Sift4G	Pathogenic	0.0010	D;D;D
Vest4		0.92
MVP		0.59
ClinPred		0.94	D
GERP RS		5.8
Varity_R		0.95
gMVP		0.97

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

Other links and lift over

dbSNP: rs56010818; hg19: chr2-38298328; COSMIC: COSV99307249; COSMIC: COSV99307249;