VCV000007737.34 - ClinVar

NM_000104.4(CYP1B1):c.171G>A (p.Trp57Ter)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(14)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000104.4(CYP1B1):c.171G>A (p.Trp57Ter)

Variation ID: 7737 Accession: VCV000007737.34

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2p22.2 2: 38075218 (GRCh38) [ NCBI UCSC ] 2: 38302361 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Oct 23, 2013	Oct 8, 2024	Mar 27, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000104.4:c.171G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000095.2:p.Trp57Ter	nonsense
NC_000002.12:g.38075218C>T
NC_000002.11:g.38302361C>T
NG_008386.2:g.5884G>A

Protein change

W57*

Other names

Canonical SPDI

NC_000002.12:38075217:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD), exomes 0.00017

The Genome Aggregation Database (gnomAD) 0.00022

Trans-Omics for Precision Medicine (TOPMed) 0.00023

Exome Aggregation Consortium (ExAC) 0.00041

Links

ClinGen: CA119014 OMIM: 601771.0010 dbSNP: rs72549387 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
CYP1B1		-	-	GRCh38 GRCh37	463	549

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Irido-corneo-trabecular dysgenesis	Pathogenic (1)	no assertion criteria provided	Mar 30, 2012	RCV000008176.8
Glaucoma 3A	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Nov 26, 2013	RCV000169657.7
CYP1B1-related disorder	Pathogenic (2)	criteria provided, single submitter	Apr 28, 2017	RCV000331073.9
Anterior segment dysgenesis 6	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Mar 27, 2024	RCV000416316.9
not provided	Pathogenic/Likely pathogenic (3)	criteria provided, multiple submitters, no conflicts	Jan 10, 2023	RCV000489919.9
Congenital glaucoma	Pathogenic (1)	criteria provided, single submitter	Jan 16, 2024	RCV000692947.9
Anterior segment dysgenesis 6 Glaucoma 3, primary infantile, B Glaucoma 3A	Pathogenic (1)	criteria provided, single submitter	Oct 31, 2018	RCV000763084.3
Anterior segment dysgenesis	Pathogenic (1)	no assertion criteria provided	Mar 31, 2020	RCV001200036.3

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Nov 26, 2013)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	Glaucoma 3A, primary open angle, congenital, juvenile, or adult onset, Peters anomaly (Autosomal recessive inheritance) Affected status: not provided Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Study: CSER-MedSeq Accession: SCV000221185.2 First in ClinVar: Apr 01, 2015 Last updated: Apr 01, 2015	Publications: PubMed (3) PubMed: 11403040‚ 19643970‚ 22004014 Comment: The Trp57X variant in CYP1B1 has been previously identified in 1 compound heterozygous individual with Peter's anomaly and secondary congenital glaucoma (Vincent 2001), in 1 … (more) The Trp57X variant in CYP1B1 has been previously identified in 1 compound heterozygous individual with Peter's anomaly and secondary congenital glaucoma (Vincent 2001), in 1 heterozygous individual with primary open angle glaucoma (Pasutto 2010), in 1 heterozygous patient with pseudoexfoliative glaucoma (Patel 2012), and was found to segregate with disease in 1 affected relative with primary open angle glaucoma (Patel 2012). This variant has been identified in 2/8428 of European American chromosomes and 2/4298 of African American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs72549387). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This nonsense variant leads to a premature termination codon at position 57, which is predicted to lead to a truncated or absent protein. In summary, this variant meets our criteria to be classified as pathogenic in a recessive manner for primary congenital glaucoma. In addition, one study reported an association between carrier status for pathogenic CYP1B1 variants and risk for adult-onset primary open angle glaucoma (Pasutto 2010). However, this study has not been replicated. (less) Number of individuals with the variant: 1
Pathogenic (Oct 31, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Glaucoma 3A Glaucoma 3, primary infantile, B Anterior segment dysgenesis 6 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000893610.1 First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019	Publications: PubMed (1) PubMed: 25741868 pmc: 4544753 pmc: 4544753 DOI: 10.1038/gim.2015.30 DOI: 10.1038/gim.2015.30
Likely pathogenic (Dec 16, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002024010.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (May 27, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics Laboratory, Skane University Hospital Lund Accession: SCV005197680.1 First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024
Pathogenic (Apr 28, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019) Method: clinical testing	CYP1B1-Related Disorders Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000430286.3 First in ClinVar: Dec 06, 2016 Last updated: May 24, 2019	Publications: PubMed (7) PubMed: 11403040‚ 24281366‚ 23218701‚ 19643970‚ 23922489‚ 12036985‚ 22004014 Comment: The CYP1B1 c.171G>A (p.Trp57Ter) variant is a stop-gained variant. Across a selection of the available literature, the p.Trp57Ter variant has been reported in at least … (more) The CYP1B1 c.171G>A (p.Trp57Ter) variant is a stop-gained variant. Across a selection of the available literature, the p.Trp57Ter variant has been reported in at least seven studies in which it was found in a compound heterozygous state in four individuals with Peters anomaly and six individuals with primary congenital glaucoma (including one set of twins), and in a heterozygous state in one individual with pseudoexfoliative glaucoma and two individuals with with juvenile open angle glaucoma, both of whom carried additional variants in another gene. The variant was also reported in a heterozygous state in three unaffected individuals (Vincent et al. 2001; Stoilov et al. 2002; Pasutto et al. 2010; Patel et al. 2012; Lim et al. 2013; Milla et al. 2013; Prokudin et al. 2014). The p.Trp57Ter variant was found in a heterozygous state in three of 1190 control alleles and is reported at a frequency of 0.00072 in the European (non-Finnish) population of the Exome Aggregation Consortium. Due to the potential impact of stop-gained variants and the collective evidence, the p.Trp57Ter variant is classified as pathogenic for CYP1B1-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
Pathogenic (-)	criteria provided, single submitter (ACGS Guidelines, 2016) Method: clinical testing	Glaucoma 3A Affected status: yes Allele origin: germline	Genomics England Pilot Project, Genomics England Accession: SCV001760088.1 First in ClinVar: Jul 27, 2021 Last updated: Jul 27, 2021
Pathogenic (Aug 25, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Anterior segment dysgenesis 6 Affected status: yes Allele origin: germline	Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota Accession: SCV001981539.1 First in ClinVar: Oct 25, 2021 Last updated: Oct 25, 2021
Pathogenic (Jan 10, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000576811.6 First in ClinVar: May 22, 2017 Last updated: Jan 21, 2023	Comment: Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This … (more) Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 14635112, 11403040, 16735994, 30653986, 23218701, 24281366, 27820421, 34758253, 12525557, 19643970, 17718864, 23922489, 27777502, 12036985, 26689913, 31980526, 31589614, 32499604, 22004014, 35170016) (less)
Pathogenic (Jan 16, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Congenital glaucoma Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000820798.7 First in ClinVar: Oct 10, 2018 Last updated: Feb 20, 2024	Publications: PubMed (12) PubMed: 28492532‚ 9097971‚ 9497261‚ 19234632‚ 11403040‚ 12036985‚ 19643970‚ 22004014‚ 23218701‚ 23922489‚ 24281366‚ 27820421 Comment: This sequence change creates a premature translational stop signal (p.Trp57) in the CYP1B1 gene. It is expected to result in an absent or disrupted protein … (more) This sequence change creates a premature translational stop signal (p.Trp57) 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 (rs72549387, gnomAD 0.04%). This premature translational stop signal has been observed in individuals with primary congenital glaucoma and primary open angle glaucoma and Peter's anomaly (PMID: 11403040, 12036985, 19643970, 22004014, 23218701, 23922489, 24281366, 27820421). ClinVar contains an entry for this variant (Variation ID: 7737). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Mar 27, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Anterior segment dysgenesis 6 Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004215451.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024
Pathogenic (Mar 30, 2012)	no assertion criteria provided Method: research	Irido-corneo-trabecular dysgenesis Affected status: yes Allele origin: paternal	Eye Genetics Research Group, Children's Medical Research Institute Accession: SCV000087413.1 First in ClinVar: Oct 23, 2013 Last updated: Oct 23, 2013	Publications: PubMed (1) PubMed: 24281366 Clinical Features: Peters anomaly (present) , anterior polar cataracts (present)
Pathogenic (May 01, 2001)	no assertion criteria provided Method: literature only	ANTERIOR SEGMENT DYSGENESIS 6, PETERS ANOMALY SUBTYPE Affected status: not provided Allele origin: germline	OMIM Accession: SCV000028381.6 First in ClinVar: Apr 04, 2013 Last updated: May 09, 2018	Publications: PubMed (1) PubMed: 11403040 Comment on evidence: For discussion of the trp57-to-ter (W57X) mutation in the CYP1B1 gene that was found in compound heterozygous state in a patient with anterior segment dysgenesis-6 … (more) For discussion of the trp57-to-ter (W57X) mutation in the CYP1B1 gene that was found in compound heterozygous state in a patient with anterior segment dysgenesis-6 (ASGD6; 617315) by Vincent et al. (2001), see 601771.0009. (less)
Pathogenic (Mar 31, 2020)	no assertion criteria provided Method: clinical testing	Anterior segment dysgenesis Affected status: yes Allele origin: biparental	Eye Genetics Research Group, Children's Medical Research Institute Accession: SCV001370528.1 First in ClinVar: Jul 16, 2020 Last updated: Jul 16, 2020 Comment: homozygote	Publications: PubMed (1) PubMed: 32499604
Pathogenic (Jan 17, 2024)	no assertion criteria provided Method: clinical testing	CYP1B1-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004121223.3 First in ClinVar: Nov 20, 2023 Last updated: Oct 08, 2024	Comment: The CYP1B1 c.171G>A variant is predicted to result in premature protein termination (p.Trp57). This variant has been reported in the compound heterozygous state in individuals … (more) The CYP1B1 c.171G>A variant is predicted to result in premature protein termination (p.Trp57). This variant has been reported in the compound heterozygous state in individuals with Peter's anomaly or congenital glaucoma (Vincent et al. 2001. PubMed ID: 11403040; Prokudin et al. 2013. PubMed ID: 24281366; Grønskov et al 2016. PubMed ID: 27820421; Millá et al. 2013. PubMed ID: 23922489), and in the heterozygous state in individuals with primary open angle glaucoma (Pasutto et al. 2010. PubMed ID: 19643970; Patel et al. 2012. PubMed ID: 22004014). This variant is reported in 0.039% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Nonsense variants in CYP1B1 are expected to be pathogenic. Given the evidence, this variant is interpreted as pathogenic for autosomal recessive disease; additionally this variant may confer a risk for the development of primary open angle glaucoma. (less)
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Comment:

The Trp57X variant in CYP1B1 has been previously identified in 1 compound heterozygous individual with Peter's anomaly and secondary congenital glaucoma (Vincent 2001), in 1 heterozygous individual with primary open angle glaucoma (Pasutto 2010), in 1 heterozygous patient with pseudoexfoliative glaucoma (Patel 2012), and was found to segregate with disease in 1 affected relative with primary open angle glaucoma (Patel 2012). This variant has been identified in 2/8428 of European American chromosomes and 2/4298 of African American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs72549387). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This nonsense variant leads to a premature termination codon at position 57, which is predicted to lead to a truncated or absent protein. In summary, this variant meets our criteria to be classified as pathogenic in a recessive manner for primary congenital glaucoma. In addition, one study reported an association between carrier status for pathogenic CYP1B1 variants and risk for adult-onset primary open angle glaucoma (Pasutto 2010). However, this study has not been replicated.

Comment:

The CYP1B1 c.171G>A (p.Trp57Ter) variant is a stop-gained variant. Across a selection of the available literature, the p.Trp57Ter variant has been reported in at least seven studies in which it was found in a compound heterozygous state in four individuals with Peters anomaly and six individuals with primary congenital glaucoma (including one set of twins), and in a heterozygous state in one individual with pseudoexfoliative glaucoma and two individuals with with juvenile open angle glaucoma, both of whom carried additional variants in another gene. The variant was also reported in a heterozygous state in three unaffected individuals (Vincent et al. 2001; Stoilov et al. 2002; Pasutto et al. 2010; Patel et al. 2012; Lim et al. 2013; Milla et al. 2013; Prokudin et al. 2014). The p.Trp57Ter variant was found in a heterozygous state in three of 1190 control alleles and is reported at a frequency of 0.00072 in the European (non-Finnish) population of the Exome Aggregation Consortium. Due to the potential impact of stop-gained variants and the collective evidence, the p.Trp57Ter variant is classified as pathogenic for CYP1B1-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

Comment:

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 14635112, 11403040, 16735994, 30653986, 23218701, 24281366, 27820421, 34758253, 12525557, 19643970, 17718864, 23922489, 27777502, 12036985, 26689913, 31980526, 31589614, 32499604, 22004014, 35170016)

Comment:

This sequence change creates a premature translational stop signal (p.Trp57*) 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 (rs72549387, gnomAD 0.04%). This premature translational stop signal has been observed in individuals with primary congenital glaucoma and primary open angle glaucoma and Peter's anomaly (PMID: 11403040, 12036985, 19643970, 22004014, 23218701, 23922489, 24281366, 27820421). ClinVar contains an entry for this variant (Variation ID: 7737). For these reasons, this variant has been classified as Pathogenic.

Comment:

The CYP1B1 c.171G>A variant is predicted to result in premature protein termination (p.Trp57*). This variant has been reported in the compound heterozygous state in individuals with Peter's anomaly or congenital glaucoma (Vincent et al. 2001. PubMed ID: 11403040; Prokudin et al. 2013. PubMed ID: 24281366; Grønskov et al 2016. PubMed ID: 27820421; Millá et al. 2013. PubMed ID: 23922489), and in the heterozygous state in individuals with primary open angle glaucoma (Pasutto et al. 2010. PubMed ID: 19643970; Patel et al. 2012. PubMed ID: 22004014). This variant is reported in 0.039% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Nonsense variants in CYP1B1 are expected to be pathogenic. Given the evidence, this variant is interpreted as pathogenic for autosomal recessive disease; additionally this variant may confer a risk for the development of primary open angle glaucoma.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Revealing hidden genetic diagnoses in the ocular anterior segment disorders.	Ma A	Genetics in medicine : official journal of the American College of Medical Genetics	2020	PMID: 32499604
CYP1B1 Mutations in Individuals With Primary Congenital Glaucoma and Residing in Denmark.	Grønskov K	Journal of glaucoma	2016	PMID: 27820421
Exome sequencing in developmental eye disease leads to identification of causal variants in GJA8, CRYGC, PAX6 and CYP1B1.	Prokudin I	European journal of human genetics : EJHG	2014	PMID: 24281366
Survey of familial glaucoma shows a high incidence of cytochrome P450, family 1, subfamily B, polypeptide 1 (CYP1B1) mutations in non-consanguineous congenital forms in a Spanish population.	Millá E	Molecular vision	2013	PMID: 23922489
CYP1B1, MYOC, and LTBP2 mutations in primary congenital glaucoma patients in the United States.	Lim SH	American journal of ophthalmology	2013	PMID: 23218701
Screening glaucoma genes in adult glaucoma suggests a multiallelic contribution of CYP1B1 to open-angle glaucoma phenotypes.	Patel HY	Clinical & experimental ophthalmology	2012	PMID: 22004014
Heterozygous loss-of-function variants in CYP1B1 predispose to primary open-angle glaucoma.	Pasutto F	Investigative ophthalmology & visual science	2010	PMID: 19643970
CYP1B1 mutations in Spanish patients with primary congenital glaucoma: phenotypic and functional variability.	Campos-Mollo E	Molecular vision	2009	PMID: 19234632
Molecular genetics of primary congenital glaucoma in Brazil.	Stoilov IR	Investigative ophthalmology & visual science	2002	PMID: 12036985
Phenotypic heterogeneity of CYP1B1: mutations in a patient with Peters' anomaly.	Vincent A	Journal of medical genetics	2001	PMID: 11403040
Sequence analysis and homology modeling suggest that primary congenital glaucoma on 2p21 results from mutations disrupting either the hinge region or the conserved core structures of cytochrome P4501B1.	Stoilov I	American journal of human genetics	1998	PMID: 9497261
Identification of three different truncating mutations in cytochrome P4501B1 (CYP1B1) as the principal cause of primary congenital glaucoma (Buphthalmos) in families linked to the GLC3A locus on chromosome 2p21.	Stoilov I	Human molecular genetics	1997	PMID: 9097971
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Text-mined citations for rs72549387 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_000104.4(CYP1B1):c.171G>A (p.Trp57Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs72549387 ...