rs72549380

Variant names:

Variant summary

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

The NM_000104.4(CYP1B1):c.1064_1076delGAGTGCAGGCAGA(p.Arg355HisfsTer69) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000203 in 1,613,104 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00020 ( 0 hom. )

Consequence

CYP1B1
NM_000104.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:15

Conservation

PhyloP100: 9.86

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:

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 exon, not predicted to undergo nonsense mediated mRNA decay. There are 75 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 2-38071277-TTCTGCCTGCACTC-T is Pathogenic according to our data. Variant chr2-38071277-TTCTGCCTGCACTC-T is described in ClinVar as [Pathogenic]. Clinvar id is 282564.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-38071277-TTCTGCCTGCACTC-T is described in Lovd as [Pathogenic]. Variant chr2-38071277-TTCTGCCTGCACTC-T is described in Lovd as [Pathogenic]. Variant chr2-38071277-TTCTGCCTGCACTC-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP1B1	NM_000104.4 link	c.1064_1076delGAGTGCAGGCAGA	p.Arg355HisfsTer69	frameshift_variant	Exon 3 of 3	ENST00000610745.5	NP_000095.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP1B1	ENST00000610745.5 link	c.1064_1076delGAGTGCAGGCAGA	p.Arg355HisfsTer69	frameshift_variant	Exon 3 of 3	1	NM_000104.4	ENSP00000478561.1		Q16678

Frequencies

GnomAD3 genomes

AF:

0.000223

AC:

AN:

152236

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:

0.000565

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000367

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000223

AC:

AN:

246644

Hom.:

AF XY:

0.000193

AC XY:

AN XY:

134434

show subpopulations

Gnomad AFR exome

AF:

0.0000659

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000329

Gnomad FIN exome

AF:

0.000185

Gnomad NFE exome

AF:

0.000371

Gnomad OTH exome

AF:

0.000494

GnomAD4 exome

AF:

0.000201

AC:

293

AN:

1460750

Hom.:

AF XY:

0.000213

AC XY:

155

AN XY:

726690

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.000246

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.000287

Gnomad4 NFE exome

AF:

0.000223

Gnomad4 OTH exome

AF:

0.000248

GnomAD4 genome

AF:

0.000223

AC:

AN:

152354

Hom.:

Cov.:

AF XY:

0.000201

AC XY:

AN XY:

74512

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:

0.000565

Gnomad4 NFE

AF:

0.000367

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000260

Hom.:

Bravo

AF:

0.000212

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Glaucoma 3A

Pathogenic:5

Oct 11, 2021

Genetics and Molecular Pathology, SA Pathology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 31, 2019

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1. -

Aug 01, 2019

Institute of Medical Molecular Genetics, University of Zurich

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Jul 28, 2023

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Arg355HisfsX69 variant in CYP1B1 has been reported in at least 2 homozygous and 4 compound heterozygous individuals with primary congenital glaucoma and segregated with disease in at least 6 affected family members from 4 families (Garcia-Anton 2017 PMID: 28448622, Campos-Mollo 2009 PMID: 19234632, Lim 2013 PMID: 23218701, Stoilov 1997 PMID: 9097971). It has been identified in 0.056% (6/10626) Finnish chromosomes by gnomAD (https://gnomad.broadinstitute.org/, v3.1.2) and has also been reported in ClinVar (Variation ID 282654). This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at position 355 and leads to a premature termination codon 69 amino acids downstream. The termination codon occurs within the last exon and is, therefore, likely to escape nonsense mediated decay (NMD) and result in a truncated protein that is missing >10% of the coding region. Loss of function of the CYP1B1 gene is an established disease mechanism in primary congenital glaucoma. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive primary congenital glaucoma. ACMG/AMP criteria applied: PVS1_Strong, PP1_Strong, PM3_Very_Strong -

Apr 01, 1997

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Anterior segment dysgenesis 6

Pathogenic:3

Mar 19, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 27, 2023

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Missense changes are a common disease-causing mechanism. Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 26148990). In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.89 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.85 (>=0.6, sensitivity 0.72 and precision 0.9)]. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000252601 /PMID: 26148990 /3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Aug 25, 2021

Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:3

Aug 31, 2015

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 07, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Frameshift variant predicted to result in abnormal protein length as the last 189 amino acids are replaced with 68 different amino acids, and other similar variants have been reported in HGMD; Also known as 1410 to 1422 delGAGTGCAGGCAGA; This variant is associated with the following publications: (PMID: 25952714, 28448622, 31980526, 27777502, 16735994, 23891399, 32832252, 10851252, 31589614, 26689913, 35170016, 37788597, 37762649, 23218701, 9097971) -

Dec 01, 2016

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Glaucoma 3A;C4310623:Anterior segment dysgenesis 6

Pathogenic:1

Jun 03, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Primary congenital glaucoma

Pathogenic:1

Aug 19, 2024

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CYP1B1 c.1064_1076del13 (p.Arg355HisfsX69) 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 0.00022 in 246644 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in CYP1B1 causing Primary Congenital Glaucoma (0.00022 vs 0.0043), allowing no conclusion about variant significance. c.1064_1076del13 has been reported in the literature in multiple individuals affected with Primary Congenital Glaucoma (example, Garcia-Anton_2017, Stoilov_1997). 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 has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 28448622, 9097971). ClinVar contains an entry for this variant (Variation ID: 282564). Based on the evidence outlined above, the variant was classified as pathogenic. -

CYP1B1-related disorder

Pathogenic:1

Aug 24, 2022

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CYP1B1 c.1064_1076del13 variant is predicted to result in a frameshift and premature protein termination (p.Arg355Hisfs*69). This variant has been reported to cause primary congenital glaucoma in both the homozygous and compound heterozygous states (Stoilov et al. 1997. PubMed ID: 9097971, alt nomenclature 1410_1422del; García-Antón et al. 2017. PubMed ID: 28448622; Capalbo A et al 2019. PubMed ID: 31589614; Hou et al. 2020. PubMed ID: 31980526). This variant is reported in 0.036% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-38298420-TTCTGCCTGCACTC-T). Frameshift variants in CYP1B1 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Congenital glaucoma

Pathogenic:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Arg355Hisfs*69) in the CYP1B1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 189 amino acid(s) of the CYP1B1 protein. This variant is present in population databases (rs72549380, gnomAD 0.04%). This premature translational stop signal has been observed in individual(s) with primary congenital glaucoma (PMID: 9097971, 28448622). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 282564). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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