ClinVar Genomic variation as it relates to human health
NM_000104.4(CYP1B1):c.1064_1076del (p.Arg355fs)
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.1064_1076del (p.Arg355fs)
Variation ID: 282564 Accession: VCV000282564.46
- Type and length
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Deletion, 13 bp
- Location
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Cytogenetic: 2p22.2 2: 38071278-38071290 (GRCh38) [ NCBI UCSC ] 2: 38298421-38298433 (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 6, 2016 May 12, 2024 Jan 29, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000104.4:c.1064_1076del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000095.2:p.Arg355fs frameshift NM_000104.3:c.1064_1076del13 NM_000104.3:c.1064_1076delGAGTGCAGGCAGA NC_000002.12:g.38071278_38071290del NC_000002.11:g.38298421_38298433del NG_008386.2:g.9812_9824del - Protein change
- R355fs
- Other names
- p.Arg355HisfsX69
- Canonical SPDI
- NC_000002.12:38071277:TCTGCCTGCACTC:
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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.
1000 Genomes Project 30x 0.00016
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00016
Trans-Omics for Precision Medicine (TOPMed) 0.00021
The Genome Aggregation Database (gnomAD), exomes 0.00022
Exome Aggregation Consortium (ExAC) 0.00023
The Genome Aggregation Database (gnomAD) 0.00024
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 (3) |
criteria provided, multiple submitters, no conflicts
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Sep 19, 2023 | RCV000260225.25 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 29, 2024 | RCV000695529.8 | |
Pathogenic (6) |
criteria provided, multiple submitters, no conflicts
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Jul 28, 2023 | RCV001250446.9 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Oct 28, 2023 | RCV001730655.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 21, 2022 | RCV002503986.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 24, 2022 | RCV004535284.1 |
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
(Aug 31, 2015)
|
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: SCV000334096.4
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
Number of individuals with the variant: 1
Sex: mixed
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Pathogenic
(Jan 29, 2024)
|
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: SCV000824035.6
First in ClinVar: Oct 10, 2018 Last updated: Feb 20, 2024 |
Comment:
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, … (more)
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. (less)
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Pathogenic
(May 31, 2019)
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criteria provided, single submitter
Method: clinical testing
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Glaucoma 3A
Affected status: yes
Allele origin:
unknown
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Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV001369133.2
First in ClinVar: Jul 04, 2020 Last updated: Dec 12, 2020 |
Comment:
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1.
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Pathogenic
(Aug 25, 2021)
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criteria provided, single submitter
Method: clinical testing
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Anterior segment dysgenesis 6
Affected status: yes
Allele origin:
germline
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Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota
Accession: SCV001981540.1
First in ClinVar: Oct 25, 2021 Last updated: Oct 25, 2021 |
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Pathogenic
(Jan 03, 2022)
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criteria provided, single submitter
Method: clinical testing
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Glaucoma 3A
Affected status: yes
Allele origin:
germline
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3billion
Accession: SCV002058821.1
First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022 |
Comment:
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 … (more)
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. (less)
Clinical Features:
Buphthalmos (present) , Glaucoma of childhood (present) , Raised intraocular pressure (present) , Epiphora (present) , Glaucoma (present) , Uveal melanoma (present) , Primary congenital … (more)
Buphthalmos (present) , Glaucoma of childhood (present) , Raised intraocular pressure (present) , Epiphora (present) , Glaucoma (present) , Uveal melanoma (present) , Primary congenital glaucoma (present) (less)
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Pathogenic
(Oct 11, 2021)
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criteria provided, single submitter
Method: clinical testing
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Glaucoma 3A
Affected status: yes
Allele origin:
germline
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Genetics and Molecular Pathology, SA Pathology
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002556849.2
First in ClinVar: Aug 04, 2022 Last updated: Dec 17, 2022 |
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Pathogenic
(Mar 21, 2022)
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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: SCV002811608.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Sep 19, 2023)
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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: SCV001167841.3
First in ClinVar: Mar 16, 2020 Last updated: Sep 30, 2023 |
Comment:
Frameshift variant predicted to result in protein truncation, as the last 189 amino acids are replaced with 68 different amino acids, and other loss-of-function variants … (more)
Frameshift variant predicted to result in protein truncation, as the last 189 amino acids are replaced with 68 different amino acids, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); This variant is associated with the following publications: (PMID: 25952714, 28448622, 31980526, 9097971, 23218701, 27777502, 16735994, 23891399, 26689913, 32832252, 31589614, 10851252, 35170016) (less)
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Pathogenic
(Aug 24, 2022)
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criteria provided, single submitter
Method: clinical testing
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CYP1B1-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004115113.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
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 … (more)
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. (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: SCV004215448.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Jul 28, 2023)
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criteria provided, single submitter
Method: clinical testing
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Glaucoma 3A
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV004847302.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
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 … (more)
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 (less)
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Pathogenic
(Dec 01, 2016)
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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: SCV001247369.21
First in ClinVar: May 09, 2020 Last updated: May 12, 2024 |
Number of individuals with the variant: 2
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Pathogenic
(Apr 01, 1997)
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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: SCV000028372.4
First in ClinVar: Apr 04, 2013 Last updated: May 29, 2021 |
Comment on evidence:
In 1 consanguineous and 1 nonconsanguineous family, Stoilov et al. (1997) demonstrated that affected individuals with primary congenital glaucoma (buphthalmos) (GLC3A; 231300) were homozygous for … (more)
In 1 consanguineous and 1 nonconsanguineous family, Stoilov et al. (1997) demonstrated that affected individuals with primary congenital glaucoma (buphthalmos) (GLC3A; 231300) were homozygous for a 13-bp deletion in the CYP1B1 gene. The deletion removed nucleotides 1410 to 1422 from exon 3 of the gene and resulted in a frameshift that truncated the open reading frame by creating a premature stop codon (TGA) 203 bp downstream of the deletion. (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:
unknown,
paternal,
maternal
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Institute of Medical Molecular Genetics, University of Zurich
Accession: SCV001424834.1
First in ClinVar: Jul 30, 2020 Last updated: Jul 30, 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
Observation 4:
Family history: yes
Segregation observed: yes
Observation 5:
Family history: yes
Segregation observed: yes
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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 |
Goniodysgenesis variability and activity of CYP1B1 genotypes in primary congenital glaucoma. | García-Antón MT | PloS one | 2017 | PMID: 28448622 |
CYP1B1, MYOC, and LTBP2 mutations in primary congenital glaucoma patients in the United States. | Lim SH | American journal of ophthalmology | 2013 | PMID: 23218701 |
CYP1B1 mutations in Spanish patients with primary congenital glaucoma: phenotypic and functional variability. | Campos-Mollo E | Molecular vision | 2009 | PMID: 19234632 |
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 |
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 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CYP1B1 | - | - | - | - |
http://www.lovd.nl/CYP1B1 | - | - | - | - |
https://portal.biobase-international.com/hgmd/pro/gene.php?gene=CYP1B1 | - | - | - | - |
Text-mined citations for rs72549380 ...
HelpRecord last updated Jun 02, 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.