rs771076928

Positions:

chr2-38074853-GC-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000104.4(CYP1B1):c.535delG(p.Ala179fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000512 in 1,563,088 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000050 ( 0 hom. )

Consequence

CYP1B1
NM_000104.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:12

Conservation

PhyloP100: -0.0270

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 18 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 123 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 2-38074853-GC-G is Pathogenic according to our data. Variant chr2-38074853-GC-G is described in ClinVar as [Pathogenic]. Clinvar id is 523943.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-38074853-GC-G is described in Lovd as [Pathogenic]. Variant chr2-38074853-GC-G 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.535delG	p.Ala179fs	frameshift_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.535delG	p.Ala179fs	frameshift_variant	2/3	1	NM_000104.4	ENSP00000478561.1		Q16678

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152238

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.0000512

AC:

AN:

156224

Hom.:

AF XY:

0.0000467

AC XY:

AN XY:

85666

show subpopulations

Gnomad AFR exome

AF:

0.000127

Gnomad AMR exome

AF:

0.000192

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:

0.0000339

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000503

AC:

AN:

1410732

Hom.:

Cov.:

AF XY:

0.0000531

AC XY:

AN XY:

697332

show subpopulations

Gnomad4 AFR exome

AF:

0.0000310

Gnomad4 AMR exome

AF:

0.000214

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000497

Gnomad4 OTH exome

AF:

0.000137

GnomAD4 genome

AF:

0.0000591

AC:

AN:

152356

Hom.:

Cov.:

AF XY:

0.0000671

AC XY:

AN XY:

74508

show subpopulations

Gnomad4 AFR

AF:

0.0000240

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.0000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Glaucoma 3A

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Jan 31, 2023	ACMG classification criteria: PVS1 very strong, PM2 supporting, PM3 strong -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 2002	- -
Pathogenic, no assertion criteria provided	research	Institute of Medical Molecular Genetics, University of Zurich	Aug 01, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Jan 03, 2022	Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000048, PM2_M). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000523943, PMID:12372064).Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

Anterior segment dysgenesis 6

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 20, 2024	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 2002	- -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 02, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 23, 2018	The c.535delG variant in the CYP1B1 gene has been reported previously in association with autosomal recessive primary congenital glaucoma, and has been reported as a founder mutation in the Moroccan population (Belmouden et al., 2002; Gronskov et al., 2016). This variant causes a frameshift starting with codon Alanine 179, changes this amino acid to an Arginine residue, and creates a premature Stop codon at position 18 of the new reading frame, denoted p.Ala179ArgfsX18. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.535delG variant is observed in 4/26120 (0.015%) alleles from individuals of Latino background and 7/182840 (0.004%) global alleles in large population cohorts, with no homozygotes identified (Lek et al., 2016). We interpret c.535delG as a pathogenic variant. -

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

Aug 30, 2021

- -

Primary congenital glaucoma

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Sep 10, 2024

Variant summary: CYP1B1 c.535delG (p.Ala179ArgfsX18) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 5.1e-05 in 156224 control chromosomes (gnomAD). c.535delG has been reported in the literature in at least an individual affected with Primary Congenital Glaucoma (example: Reis_2016). These data indicate that the variant may be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 27272408). ClinVar contains an entry for this variant (Variation ID: 523943). Based on the evidence outlined above, the variant was classified as pathogenic. -

CYP1B1-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 07, 2023

The CYP1B1 c.535delG variant is predicted to result in a frameshift and premature protein termination (p.Ala179Argfs*18). This variant was reported in the homozygous or compound heterozygous state to be causative for primary congenital glaucoma (described as 4339delG, Bouyacoub et al. 2014. PubMed ID: 24942078; Cardoso et al. 2015. PubMed ID: 25952714; García-Antón et al. 2017. PubMed ID: 28448622). This variant is reported in 0.019% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-38301996-GC-G). Frameshift variants in CYP1B1 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Congenital glaucoma

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 21, 2023

This sequence change creates a premature translational stop signal (p.Ala179Argfs*18) in the CYP1B1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CYP1B1 are known to be pathogenic (PMID: 9097971, 9497261, 19234632). This variant is present in population databases (rs771076928, gnomAD 0.02%). This premature translational stop signal has been observed in individuals with open-angle glaucoma, and primary congenital glaucoma (PMID: 12372064, 19234632, 23922489, 27272408, 27777502, 27820421). It has also been observed to segregate with disease in related individuals. This variant is also known as c.4339delG, c.906delG, c.534_535delG (p.Ala179ArgfsX16). ClinVar contains an entry for this variant (Variation ID: 523943). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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