rs72549380

Positions:

• chr2-38071277-TTCTGCCTGCACTC-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000104.4(CYP1B1):​c.1064_1076del​(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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:15
• Conservation: PhyloP100: 9.86

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.

• 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/exons	MANE	Protein	UniProt
CYP1B1	NM_000104.4	c.1064_1076del	p.Arg355HisfsTer69	frameshift_variant	3/3	ENST00000610745.5	NP_000095.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP1B1	ENST00000610745.5	c.1064_1076del	p.Arg355HisfsTer69	frameshift_variant	3/3	1	NM_000104.4	ENSP00000478561	P1

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

GnomAD3 exomes AF: 0.000223 AC: 55 AN: 246644 Hom.: 0 AF XY: 0.000193 AC XY: 26 AN XY: 134434

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

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

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.: 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:6

Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	May 31, 2019	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1. -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Oct 11, 2021	- -
Pathogenic, no assertion criteria provided	research	Institute of Medical Molecular Genetics, University of Zurich	Aug 01, 2019	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 1997	- -
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 protein truncation. Multiple pathogenic variants are reported in the predicted truncated region (PVS1_S). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000282564, PMID:9097971, 3billion dataset). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000227, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 28, 2023	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 -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 31, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 07, 2024	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) -

Anterior segment dysgenesis 6 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 19, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota	Aug 25, 2021	- -

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

Mar 21, 2022

- -

Primary congenital glaucoma Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Aug 19, 2024

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

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 24, 2022

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

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

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs72549380; hg19: chr2-38298420;