ClinVar Genomic variation as it relates to human health
NM_000104.4(CYP1B1):c.1159G>A (p.Glu387Lys)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000104.4(CYP1B1):c.1159G>A (p.Glu387Lys)
Variation ID: 7735 Accession: VCV000007735.38
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2p22.2 2: 38071195 (GRCh38) [ NCBI UCSC ] 2: 38298338 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Dec 26, 2017 May 12, 2024 Jan 25, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000104.4:c.1159G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000095.2:p.Glu387Lys missense NC_000002.12:g.38071195C>T NC_000002.11:g.38298338C>T NG_008386.2:g.9907G>A Q16678:p.Glu387Lys - Protein change
- E387K
- Other names
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- Canonical SPDI
- NC_000002.12:38071194:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe 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.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00018
Trans-Omics for Precision Medicine (TOPMed) 0.00025
The Genome Aggregation Database (gnomAD), exomes 0.00029
Exome Aggregation Consortium (ExAC) 0.00034
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 | ||
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HI score
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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. |
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CYP1B1 | - | - |
GRCh38 GRCh37 |
443 | 526 |
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. |
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Pathogenic/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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May 14, 2020 | RCV000008174.15 | |
Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Aug 12, 2022 | RCV000724653.23 | |
Pathogenic (1) |
criteria provided, single submitter
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May 13, 2017 | RCV000791358.6 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 25, 2024 | RCV001201386.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 9, 2021 | RCV001375550.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 27, 2021 | RCV002490338.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 28, 2023 | RCV003466834.1 |
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. |
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Pathogenic
(May 13, 2017)
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criteria provided, single submitter
Method: clinical testing
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Glaucoma 3A
(Autosomal recessive inheritance)
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000712165.1
First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018 |
Comment:
The p.Glu387Lys variant in CYP1B1 is a well-established pathogenic variant for p rimary congenital glaucoma, and represents a founder variant in the Slovak Roman i … (more)
The p.Glu387Lys variant in CYP1B1 is a well-established pathogenic variant for p rimary congenital glaucoma, and represents a founder variant in the Slovak Roman i population (Azmanov 2011, Kelbermann 2011, Li 2011, Lim 2013, Plasilova 1999, Reis 2016, Sivadorai 2008). In vitro functional studies support that the p.Glu38 7Lys variant impacts protein function (Banjeree 2016 and Lopez-Garrido 2013). Th is variant has also been identified in 36/64286 European chromosomes by the Exom e Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs55989760 ); however, this frequency is low enough to be consistent with a recessive carri er frequency. In summary, the p.Glu387Lys variant meets criteria to be classifie d as pathogenic for primary congenital glaucoma in an autosomal recessive manner . (less)
Number of individuals with the variant: 1
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Glaucoma 3A
Affected status: unknown
Allele origin:
germline
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Baylor Genetics
Accession: SCV001162948.1
First in ClinVar: Feb 29, 2020 Last updated: Feb 29, 2020 |
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Pathogenic
(Apr 09, 2021)
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criteria provided, single submitter
Method: clinical testing
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Primary congenital glaucoma
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001572419.1
First in ClinVar: Apr 30, 2021 Last updated: Apr 30, 2021 |
Comment:
Variant summary: CYP1B1 c.1159G>A (p.Glu387Lys) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging … (more)
Variant summary: CYP1B1 c.1159G>A (p.Glu387Lys) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00036 in 249726 control chromosomes (gnomAD and publication data). This frequency is not higher than expected for a pathogenic variant in CYP1B1 causing Primary Congenital Glaucoma (0.00036 vs 0.0043), allowing no conclusion about variant significance. c.1159G>A has been reported in the literature in multiple individuals affected with Primary Congenital Glaucoma and Primary open-angle glaucoma. Moreover, the variant was shown to co-segregate with disease in several different families (Stoilov_1998, Plasilova_1999, Lopez-Garrido_2012, Melki_2004). These data indicate that the variant is very likely to be associated with disease. In addition, this variant has been reported as a founder variant in Slovak Gypsies (Roms) (Plasilova_1999). Functional studies report this variant results in having significantly reduced enzyme activity (Lopez-Garrido_2012, Banerjee_2016). Five ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Likely pathogenic
(May 14, 2020)
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criteria provided, single submitter
Method: clinical testing
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Glaucoma 3A
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
maternal
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Genomic Medicine Lab, University of California San Francisco
Study: CSER-P3EGS
Accession: SCV001572946.1 First in ClinVar: May 05, 2021 Last updated: May 05, 2021 |
Sex: male
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Pathogenic
(Dec 27, 2021)
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criteria provided, single submitter
Method: clinical testing
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Glaucoma 3A
Glaucoma 3, primary infantile, B Anterior segment dysgenesis 6
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002784513.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Aug 12, 2022)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV003819395.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 25, 2024)
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criteria provided, single submitter
Method: clinical testing
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Congenital glaucoma
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000626998.4
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 387 of the CYP1B1 protein … (more)
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 387 of the CYP1B1 protein (p.Glu387Lys). This variant is present in population databases (rs55989760, gnomAD 0.05%). This missense change has been observed in individual(s) with primary congenital glaucoma (PCG) (PMID: 9497261, 10227395, 15342693, 18414103, 21081970, 21600657, 23218183, 25109919, 27272408, 27820421). It is commonly reported in individuals of Slovak ancestry (PMID: 9497261, 10227395, 15342693, 18414103, 21081970, 21600657, 23218183, 25109919, 27272408, 27820421). ClinVar contains an entry for this variant (Variation ID: 7735). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CYP1B1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects CYP1B1 function (PMID: 18227148, 23218183, 27243976). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jun 01, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001747947.15
First in ClinVar: Jul 10, 2021 Last updated: May 12, 2024 |
Number of individuals with the variant: 1
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Pathogenic
(Aug 02, 2018)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000331834.4
First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 2
Sex: mixed
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Pathogenic
(Aug 05, 2021)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV002512881.2
First in ClinVar: May 21, 2022 Last updated: Mar 04, 2023 |
Comment:
Recognized as founder variant in the Slovak Roman population (Plasilova et al., 1999); Published functional studies demonstrate a damaging effect whereby enzymatic activity was evaluated … (more)
Recognized as founder variant in the Slovak Roman population (Plasilova et al., 1999); Published functional studies demonstrate a damaging effect whereby enzymatic activity was evaluated in transiently transfected HEK-293T cells. The mutant protein was completely inactive. The levels of mutant CYP1B1 were slightly lower than wild-type, indicating reduced stability. (Lopez-Garrido et al., 2013); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 19204079, 25109919, 10227395, 9497261, 27243976, 27820421, 27272408, 28448622, 16735994, 23218701, 21854771, 21600657, 31453292, 31980526, 32832252, 31589614, 10851252, 23218183) (less)
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Pathogenic
(Oct 28, 2023)
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criteria provided, single submitter
Method: clinical testing
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Anterior segment dysgenesis 6
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004215450.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Jul 01, 2008)
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no assertion criteria provided
Method: literature only
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GLAUCOMA 3, PRIMARY CONGENITAL, A
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000028379.4
First in ClinVar: Apr 04, 2013 Last updated: May 21, 2018 |
Comment on evidence:
Plasilova et al. (1999) reported mutation screening of 43 patients from 26 Slovak Rom (Gypsy) families. The Slovak Rom population is known to have an … (more)
Plasilova et al. (1999) reported mutation screening of 43 patients from 26 Slovak Rom (Gypsy) families. The Slovak Rom population is known to have an unusually high frequency of primary congenital glaucoma (231300). A homozygous G-to-A transition at nucleotide 1505 in a highly conserved region of exon 3 was detected in all families. This resulted in a lysine-to-glutamine substitution, affecting the conserved K helix region of the CYP1B1 molecule. This mutation appeared on a common haplotype in all patients. Plasilova et al. (1999) concluded that this mutation originated from a single ancestral mutational event. Sivadorai et al. (2008) analyzed the CYP1B1 gene in 21 patients from 16 unrelated Bulgarian Gypsy families and detected 5 different mutations. The E387K mutation was detected in only 3 (8%) of 38 mutant alleles, and only 4 (0.56%) of 715 healthy Gypsy controls were heterozygous for the E387K mutation. Sivadorai et al. (2008) concluded that the molecular basis of primary congenital glaucoma in the Gypsy population is unresolved and that diagnostic analysis must extend beyond the E387K mutation. (less)
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Pathogenic
(Aug 01, 2019)
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no assertion criteria provided
Method: research
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Glaucoma 3A
Affected status: yes, no
Allele origin:
germline,
unknown
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Institute of Medical Molecular Genetics, University of Zurich
Accession: SCV001424838.1
First in ClinVar: Jul 29, 2020 Last updated: Jul 29, 2020 |
Observation 1:
Family history: yes
Segregation observed: yes
Observation 2:
Family history: yes
Segregation observed: yes
Observation 3:
Family history: yes
Segregation observed: yes
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not provided
(-)
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no classification provided
Method: literature only
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Glaucoma 3A
Affected status: unknown
Allele origin:
germline
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GeneReviews
Accession: SCV002106341.2
First in ClinVar: Mar 19, 2022 Last updated: Oct 01, 2022 |
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Exome Sequencing in a Swiss Childhood Glaucoma Cohort Reveals CYP1B1 and FOXC1 Variants as Most Frequent Causes. | Lang E | Translational vision science & technology | 2020 | PMID: 32832252 |
Primary Congenital Glaucoma. | Adam MP | - | 2017 | PMID: 20301314 |
CYP1B1 Mutations in Individuals With Primary Congenital Glaucoma and Residing in Denmark. | Grønskov K | Journal of glaucoma | 2016 | PMID: 27820421 |
Whole exome sequencing identifies multiple diagnoses in congenital glaucoma with systemic anomalies. | Reis LM | Clinical genetics | 2016 | PMID: 27272408 |
Functional and Structural Analyses of CYP1B1 Variants Linked to Congenital and Adult-Onset Glaucoma to Investigate the Molecular Basis of These Diseases. | Banerjee A | PloS one | 2016 | PMID: 27243976 |
[Homozygous E387K (1159G>A) mutation of the CYP1B1 gene in a Roma boy affected with primary congenital glaucoma. Case report]. | Vogt G | Orvosi hetilap | 2014 | PMID: 25109919 |
CYP1B1, MYOC, and LTBP2 mutations in primary congenital glaucoma patients in the United States. | Lim SH | American journal of ophthalmology | 2013 | PMID: 23218701 |
Null CYP1B1 genotypes in primary congenital and nondominant juvenile glaucoma. | López-Garrido MP | Ophthalmology | 2013 | PMID: 23218183 |
Overview of Cytochrome P450 1B1 gene mutations in patients with primary congenital glaucoma. | Li N | Experimental eye research | 2011 | PMID: 21854771 |
CYP1B1-related anterior segment developmental anomalies novel mutations for infantile glaucoma and von Hippel's ulcer revisited. | Kelberman D | Ophthalmology | 2011 | PMID: 21600657 |
LTBP2 and CYP1B1 mutations and associated ocular phenotypes in the Roma/Gypsy founder population. | Azmanov DN | European journal of human genetics : EJHG | 2011 | PMID: 21081970 |
Genetic heterogeneity and minor CYP1B1 involvement in the molecular basis of primary congenital glaucoma in Gypsies. | Sivadorai P | Clinical genetics | 2008 | PMID: 18537981 |
Contribution of CYP1B1 mutations and founder effect to primary congenital glaucoma in Mexico. | Zenteno JC | Journal of glaucoma | 2008 | PMID: 18414103 |
Metabolism of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) by human CYP1B1 genetic variants. | Han JF | Drug metabolism and disposition: the biological fate of chemicals | 2008 | PMID: 18227148 |
Primary congenital glaucoma and Rieger's anomaly: extended haplotypes reveal founder effects for eight distinct CYP1B1 mutations. | Chavarria-Soley G | Molecular vision | 2006 | PMID: 16735994 |
CYP1B1 mutations in French patients with early-onset primary open-angle glaucoma. | Melki R | Journal of medical genetics | 2004 | PMID: 15342693 |
Identification of a single ancestral CYP1B1 mutation in Slovak Gypsies (Roms) affected with primary congenital glaucoma. | Plásilová M | Journal of medical genetics | 1999 | PMID: 10227395 |
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 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CYP1B1 | - | - | - | - |
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Text-mined citations for rs55989760 ...
HelpRecord last updated May 12, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.