rs72549380

Variant names:

• chr2-38071277-TTCTGCCTGCACTC-T
• rs72549380
• NM_000104.4:c.1064_1076delGAGTGCAGGCAGA

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_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. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. 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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:15
• Conservation: PhyloP100: 9.86
• Publications: 14 publications found

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 Gene-Disease associations (from GenCC):

• CYP1B1-related glaucoma with or without anterior segment dysgenesis

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen, Ambry Genetics
• glaucoma 3A

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, G2P
• anterior segment dysgenesis 6

  Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia
• congenital glaucoma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Peters anomaly

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 16 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 46 pathogenic variants in the truncated region.
• PP5: Variant 2-38071277-TTCTGCCTGCACTC-T is Pathogenic according to our data. Variant chr2-38071277-TTCTGCCTGCACTC-T is described in ClinVar as Pathogenic. ClinVar VariationId is 282564.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000104.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP1B1	NM_000104.4	MANE Select	c.1064_1076delGAGTGCAGGCAGA	p.Arg355HisfsTer69	frameshift	Exon 3 of 3	NP_000095.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP1B1	ENST00000610745.5	TSL:1 MANE Select	c.1064_1076delGAGTGCAGGCAGA	p.Arg355HisfsTer69	frameshift	Exon 3 of 3	ENSP00000478561.1
	CYP1B1	ENST00000490576.2	TSL:4	c.1064_1076delGAGTGCAGGCAGA	p.Arg355HisfsTer69	frameshift	Exon 3 of 3	ENSP00000478839.2
	CYP1B1	ENST00000614273.1	TSL:5	c.1064_1076delGAGTGCAGGCAGA	p.Arg355HisfsTer69	frameshift	Exon 3 of 3	ENSP00000483678.1

Frequencies

GnomAD3 genomes AF: 0.000223 AC: 34 AN: 152236 Hom.: 0 Cov.: 32

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

GnomAD2 exomes AF: 0.000223 AC: 55 AN: 246644 AF XY: 0.000193

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 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.: 0 AF XY: 0.000213 AC XY: 155 AN XY: 726690

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000896 AC: 3 AN: 33480

American (AMR) AF: 0.000246 AC: 11 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86256

European-Finnish (FIN) AF: 0.000287 AC: 15 AN: 52314

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000223 AC: 248 AN: 1111990

Other (OTH) AF: 0.000248 AC: 15 AN: 60384

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000223 AC: 34 AN: 152354 Hom.: 0 Cov.: 32 AF XY: 0.000201 AC XY: 15 AN XY: 74512

African (AFR) AF: 0.0000240 AC: 1 AN: 41590

American (AMR) AF: 0.000131 AC: 2 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.000565 AC: 6 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000367 AC: 25 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000260 Hom.: 0

Bravo AF: 0.000212

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glaucoma 3A Pathogenic:5

Apr 01, 1997

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Oct 11, 2021

Genetics and Molecular Pathology, SA Pathology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aug 01, 2019

Institute of Medical Molecular Genetics, University of Zurich

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

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.

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

Anterior segment dysgenesis 6 Pathogenic:3

Aug 25, 2021

Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 19, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 28, 2024

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v4.1.0 dataset (total allele frequency: 0.020%). Predicted Consequence/Location: Frameshift: predicted to result in a loss or disruption of normal protein function through protein truncation. The predicted truncated protein may be shortened by more than 10%. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000282564 /PMID: 9097971 /3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

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 v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.9
Mutation Taster		=3/197	disease causing (ClinVar)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs72549380; hg19: chr2-38298420;