VCV000007730.57 - ClinVar

NM_000104.4(CYP1B1):c.182G>A (p.Gly61Glu)

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.

(19)

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

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.182G>A (p.Gly61Glu)

Variation ID: 7730 Accession: VCV000007730.57

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2p22.2 2: 38075207 (GRCh38) [ NCBI UCSC ] 2: 38302350 (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	Dec 19, 2017	Oct 20, 2024	Jul 31, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000104.4:c.182G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000095.2:p.Gly61Glu	missense
NC_000002.12:g.38075207C>T
NC_000002.11:g.38302350C>T
NG_008386.2:g.5895G>A
	Q16678:p.Gly61Glu

... more HGVS ... less HGVS

Protein change

G61E

Other names

Canonical SPDI

NC_000002.12:38075206: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) 0.00017

Trans-Omics for Precision Medicine (TOPMed) 0.00034

Exome Aggregation Consortium (ExAC) 0.00069

Links

ClinGen: CA254237 UniProtKB: Q16678#VAR_001244 OMIM: 601771.0003 dbSNP: rs28936700 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	462	548

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.
not provided	Pathogenic (4)	criteria provided, multiple submitters, no conflicts	Feb 28, 2023	RCV000255452.32
Glaucoma 3A	Pathogenic (8)	criteria provided, multiple submitters, no conflicts	Mar 17, 2024	RCV000008169.25
Anterior segment dysgenesis 6 Glaucoma 3, primary infantile, B Glaucoma 3A	Pathogenic (1)	criteria provided, single submitter	Mar 24, 2022	RCV000763083.4
Congenital glaucoma	Pathogenic (1)	criteria provided, single submitter	Jan 31, 2024	RCV001206715.8
Anterior segment dysgenesis 6	Pathogenic (2)	criteria provided, single submitter	Mar 26, 2024	RCV001335112.5
Anterior segment dysgenesis 6 Glaucoma 3A	Uncertain significance (1)	no assertion criteria provided	-	RCV003483427.1
Primary congenital glaucoma	Pathogenic (1)	criteria provided, single submitter	Jul 31, 2024	RCV004700202.1
CYP1B1-related disorder	Pathogenic (1)	no assertion criteria provided	Jul 9, 2024	RCV004732534.1

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.
Pathogenic (Feb 01, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen Accession: SCV001480127.1 First in ClinVar: Feb 20, 2021 Last updated: Feb 20, 2021	Clinical Features: Microcephaly (present) , Blindness (present) , Global developmental delay (present) , Severe expressive language delay (present) Sex: male
Pathogenic (Mar 24, 2022)	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: SCV000893609.2 First in ClinVar: Mar 31, 2019 Last updated: Dec 31, 2022	Publications: PubMed (1) PubMed: 25741868 pmc: 4544753 pmc: 4544753 DOI: 10.1038/gim.2015.30 DOI: 10.1038/gim.2015.30
Pathogenic (Feb 28, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002018104.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (Jan 31, 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: SCV001378037.4 First in ClinVar: Jul 16, 2020 Last updated: Feb 20, 2024	Publications: PubMed (6) PubMed: 9463332‚ 12372064‚ 19234632‚ 18470941‚ 19793111‚ 27243976 Comment: This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 61 of the CYP1B1 protein … (more) This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 61 of the CYP1B1 protein (p.Gly61Glu). This variant is present in population databases (rs28936700, gnomAD 0.04%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individuals with primary congenital glaucoma (PMID: 9463332, 12372064, 19234632). It is commonly reported in individuals of Saudi and Moroccan ancestry (PMID: 9463332, 12372064, 19234632). This variant is also known as c.3987G>A. ClinVar contains an entry for this variant (Variation ID: 7730). 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 80%. Experimental studies have shown that this missense change affects CYP1B1 function (PMID: 18470941, 19793111, 27243976). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Mar 17, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Glaucoma 3A Affected status: unknown Allele origin: germline	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center Accession: SCV004847100.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Glaucoma 3A Affected status: unknown Allele origin: germline	Baylor Genetics Accession: SCV001162951.1 First in ClinVar: Feb 29, 2020 Last updated: Feb 29, 2020
Pathogenic (May 18, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Glaucoma 3A Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV001623487.1 First in ClinVar: May 23, 2021 Last updated: May 23, 2021	Sex: mixed
Pathogenic (Mar 03, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000321539.8 First in ClinVar: Oct 09, 2016 Last updated: Mar 04, 2023	Comment: Published functional studies demonstrate a damaging effect, specifically, the variant causes reduced enzyme activity and decreased protein stability (Chavarria-Soley et al., 2008; Lopez-Garrido et al., … (more) Published functional studies demonstrate a damaging effect, specifically, the variant causes reduced enzyme activity and decreased protein stability (Chavarria-Soley et al., 2008; Lopez-Garrido et al., 2010); Known as a Middle Eastern founder mutation (Li et al., 2011); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 32153331, 33745036, 26982174, 27243976, 9463332, 9497261, 31024815, 21854771, 25091052, 19793111, 24591815, 19204079, 18470941, 19643970, 24210336, 21596299, 19234632, 12372064, 26164761, 24099281, 23363883, 25261878, 28448622, 16862072, 30127590, 30207287, 30270463, 31980526, 34426522, 31589614, 15621878, 15037581, 33170892) (less)
Pathogenic (Mar 26, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Anterior segment dysgenesis 6 Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV001528169.2 First in ClinVar: Mar 22, 2021 Last updated: Jun 17, 2024
Pathogenic (Jun 24, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Glaucoma 3A (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV002557822.2 First in ClinVar: Aug 08, 2022 Last updated: Jul 23, 2024	Publications: PubMed (3) PubMed: 19234632‚ 19744731‚ 26550445 Comment: Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism … (more) Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with congenital, juvenile, or adult onset primary open anglet glaucoma 3A (MIM#231300) and anterior segment dysgenesis 6, multiple subtypes (MIM#617315). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0112 - The condition associated with this gene has incomplete penetrance (PMID: 26550445, 19744731). (I) 0115 - Variants in this gene are known to have variable expressivity. Individuals with the same variants have been reported with variable severity and age of onset (PMID: 19744731). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to glutamic acid. (I) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (63 heterozygotes, 2 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated p450 domain (DECIPHER). (I) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. The p.(Gly61Arg) variant has been classified as pathogenic by a clinical laboratory in ClinVar. (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been observed in homozygous or compound heterozygous state in many individuals with primary congenital glaucoma, and has been described as hypomorphic due to its residual enzyme activity and reduced penentrance (ClinVar, DECIPHER, PMIDs: 19234632, 19744731). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. This variant has been shown to have 25% of wild type activity and significantly reduced protein expression using fluorimetric and western blot assays on transfected HEK-293T cells (PMID: 19234632). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
Pathogenic (Jul 31, 2024)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Primary congenital glaucoma Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV005202335.1 First in ClinVar: Sep 16, 2024 Last updated: Sep 16, 2024	Publications: PubMed (1) PubMed: 9463332 Comment: Variant summary: CYP1B1 c.182G>A (p.Gly61Glu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging … (more) Variant summary: CYP1B1 c.182G>A (p.Gly61Glu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00032 in 198162 control chromosomes in the gnomAD database, including 2 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in CYP1B1 causing Primary Congenital Glaucoma (0.00032 vs 0.0043), allowing no conclusion about variant significance. c.182G>A has been reported in the literature in multiple individuals affected with Primary Congenital Glaucoma (Bejjani_1998). These data indicate that the variant is very likely to be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 9463332). ClinVar contains an entry for this variant (Variation ID: 7730). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
Pathogenic (Feb 01, 2022)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001247370.26 First in ClinVar: May 09, 2020 Last updated: Oct 20, 2024	Number of individuals with the variant: 2
Pathogenic (Aug 25, 2019)	no assertion criteria provided Method: clinical testing	Glaucoma 3A Affected status: yes Allele origin: germline	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City Accession: SCV001132972.1 First in ClinVar: Jan 04, 2020 Last updated: Jan 04, 2020
Pathogenic (Oct 01, 2002)	no assertion criteria provided Method: literature only	ANTERIOR SEGMENT DYSGENESIS 6, PETERS ANOMALY SUBTYPE Affected status: not provided Allele origin: germline	OMIM Accession: SCV001652917.2 First in ClinVar: May 29, 2021 Last updated: Dec 17, 2022	Publications: PubMed (4) PubMed: 9463332‚ 9497261‚ 12372064‚ 15621878 Comment on evidence: Glaucoma 3, Primary Congenital, A In 17 of 24 Saudi Arabian families, Bejjani et al. (1998) found that primary congenital glaucoma (GLC3A; 231300) was associated … (more) Glaucoma 3, Primary Congenital, A In 17 of 24 Saudi Arabian families, Bejjani et al. (1998) found that primary congenital glaucoma (GLC3A; 231300) was associated with homozygosity for a 3987G-A transition in exon 2 of the CYP1B1 gene, leading to a gly61-to-glu (G61E) amino acid substitution. In 3 other families, affected members were compound heterozygotes for this mutation and 2 other missense mutations in exon 3 (601771.0006 and 601771.0007, respectively). In 4 separate Turkish families with primary congenital glaucoma (PCG), Stoilov et al. (1998) found that 5 PCG chromosomes carried a G-to-A transition at nucleotide 528, predicted to result in a G61E substitution at the hinge region of the CYP1B1 protein. In Morocco, Belmouden et al. (2002) studied 32 unrelated patients with PCG and identified 2 mutations in 11 (34%) patients: the G61E mutation and a 4339delG mutation (601771.0011). Two patients were homozygous for G61E and 7 others for 4339delG, whereas the remaining 2 were compound heterozygotes. Anterior Segment Dysgenesis 6, Peters Anomaly Subtype In 5 patients with Peters anomaly (ASGD6; 617315) from 4 consanguineous Saudi Arabian families, including a brother (PE-10) and sister (PE-11) from a previously reported PCG pedigree (KKECG-122; Bejjani et al., 1998), Edward et al. (2004) identified homozygosity for the G61E mutation in the CYP1B1 gene. Noting that homozygosity for CYP1B1 mutations had been detected in individuals within families who were clinically unaffected, had classic PCG, or had Peters anomaly, Edward et al. (2004) suggested the existence of modifiers of the ocular phenotype that could either mitigate or worsen the deleterious effects of CYP1B1 mutations. (less)
Pathogenic (Oct 01, 2002)	no assertion criteria provided Method: literature only	GLAUCOMA 3, PRIMARY CONGENITAL, A Affected status: not provided Allele origin: germline	OMIM Accession: SCV000028374.10 First in ClinVar: Apr 04, 2013 Last updated: Dec 17, 2022	Publications: PubMed (4) PubMed: 9463332‚ 9497261‚ 12372064‚ 15621878 Comment on evidence: Glaucoma 3, Primary Congenital, A In 17 of 24 Saudi Arabian families, Bejjani et al. (1998) found that primary congenital glaucoma (GLC3A; 231300) was associated … (more) Glaucoma 3, Primary Congenital, A In 17 of 24 Saudi Arabian families, Bejjani et al. (1998) found that primary congenital glaucoma (GLC3A; 231300) was associated with homozygosity for a 3987G-A transition in exon 2 of the CYP1B1 gene, leading to a gly61-to-glu (G61E) amino acid substitution. In 3 other families, affected members were compound heterozygotes for this mutation and 2 other missense mutations in exon 3 (601771.0006 and 601771.0007, respectively). In 4 separate Turkish families with primary congenital glaucoma (PCG), Stoilov et al. (1998) found that 5 PCG chromosomes carried a G-to-A transition at nucleotide 528, predicted to result in a G61E substitution at the hinge region of the CYP1B1 protein. In Morocco, Belmouden et al. (2002) studied 32 unrelated patients with PCG and identified 2 mutations in 11 (34%) patients: the G61E mutation and a 4339delG mutation (601771.0011). Two patients were homozygous for G61E and 7 others for 4339delG, whereas the remaining 2 were compound heterozygotes. Anterior Segment Dysgenesis 6, Peters Anomaly Subtype In 5 patients with Peters anomaly (ASGD6; 617315) from 4 consanguineous Saudi Arabian families, including a brother (PE-10) and sister (PE-11) from a previously reported PCG pedigree (KKECG-122; Bejjani et al., 1998), Edward et al. (2004) identified homozygosity for the G61E mutation in the CYP1B1 gene. Noting that homozygosity for CYP1B1 mutations had been detected in individuals within families who were clinically unaffected, had classic PCG, or had Peters anomaly, Edward et al. (2004) suggested the existence of modifiers of the ocular phenotype that could either mitigate or worsen the deleterious effects of CYP1B1 mutations. (less)
Uncertain significance (-)	no assertion criteria provided Method: clinical testing	Glaucoma 3A Anterior segment dysgenesis 6 Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Coban-Akdemir Lab, University of Texas Health Science Center Accession: SCV004231748.1 First in ClinVar: Jan 26, 2024 Last updated: Jan 26, 2024	Comment: The affected individual was severely delayed with no communication skills and died at a young age. Since the subject was deceased, we could not perform … (more) The affected individual was severely delayed with no communication skills and died at a young age. Since the subject was deceased, we could not perform an ophthalmologic evaluation. (less) Sex: male Ethnicity/Population group: Turkish Comment on evidence: The variant was also reported in a Turkish patient with primary congenital glaucoma (PMID: 9497261).
Pathogenic (Jul 09, 2024)	no assertion criteria provided Method: clinical testing	CYP1B1-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV005349246.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Comment: The CYP1B1 c.182G>A variant is predicted to result in the amino acid substitution p.Gly61Glu. This variant in compound heterozygous and homozygous states has been reported … (more) The CYP1B1 c.182G>A variant is predicted to result in the amino acid substitution p.Gly61Glu. This variant in compound heterozygous and homozygous states has been reported to be causative for primary congenital glaucoma (PCG) (Bejjani et al. 1998. PubMed ID: 9463332; Abu-Amero et al. 2015. PubMed ID: 24099281; Micheal et al. 2015. PubMed ID: 25091052; Stoilov et al. 1998. PubMed ID: 9497261). This variant was seen in 78% of the PCG chromosomes analyzed and reported as a common variant in the Saudi Arabian population (Bejjani et al. 1998. PubMed ID: 9463332, reported as 3987G>A change). Functional studies have shown that this variant significantly reduces enzyme activity (Banerjee et al. 2016. PubMed ID: 27243976). This variant is reported in 0.041% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. (less)
Pathogenic (Jun 12, 2024)	no assertion criteria provided Method: curation	Glaucoma 3A Affected status: yes Allele origin: unknown	Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University Accession: SCV000891494.2 First in ClinVar: Sep 03, 2018 Last updated: Jun 23, 2024	Geographic origin: Middle East
not provided (-)	no classification provided Method: literature only	Glaucoma 3A Affected status: unknown Allele origin: germline	GeneReviews Accession: SCV002106340.2 First in ClinVar: Mar 19, 2022 Last updated: Oct 01, 2022	Publications: BookShelf: NBK1135 BookShelf: NBK1135
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Comment:

This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 61 of the CYP1B1 protein (p.Gly61Glu). This variant is present in population databases (rs28936700, gnomAD 0.04%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individuals with primary congenital glaucoma (PMID: 9463332, 12372064, 19234632). It is commonly reported in individuals of Saudi and Moroccan ancestry (PMID: 9463332, 12372064, 19234632). This variant is also known as c.3987G>A. ClinVar contains an entry for this variant (Variation ID: 7730). 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 80%. Experimental studies have shown that this missense change affects CYP1B1 function (PMID: 18470941, 19793111, 27243976). For these reasons, this variant has been classified as Pathogenic.

Comment:

Published functional studies demonstrate a damaging effect, specifically, the variant causes reduced enzyme activity and decreased protein stability (Chavarria-Soley et al., 2008; Lopez-Garrido et al., 2010); Known as a Middle Eastern founder mutation (Li et al., 2011); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 32153331, 33745036, 26982174, 27243976, 9463332, 9497261, 31024815, 21854771, 25091052, 19793111, 24591815, 19204079, 18470941, 19643970, 24210336, 21596299, 19234632, 12372064, 26164761, 24099281, 23363883, 25261878, 28448622, 16862072, 30127590, 30207287, 30270463, 31980526, 34426522, 31589614, 15621878, 15037581, 33170892)

Comment:

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with congenital, juvenile, or adult onset primary open anglet glaucoma 3A (MIM#231300) and anterior segment dysgenesis 6, multiple subtypes (MIM#617315). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0112 - The condition associated with this gene has incomplete penetrance (PMID: 26550445, 19744731). (I) 0115 - Variants in this gene are known to have variable expressivity. Individuals with the same variants have been reported with variable severity and age of onset (PMID: 19744731). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to glutamic acid. (I) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (63 heterozygotes, 2 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated p450 domain (DECIPHER). (I) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. The p.(Gly61Arg) variant has been classified as pathogenic by a clinical laboratory in ClinVar. (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been observed in homozygous or compound heterozygous state in many individuals with primary congenital glaucoma, and has been described as hypomorphic due to its residual enzyme activity and reduced penentrance (ClinVar, DECIPHER, PMIDs: 19234632, 19744731). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. This variant has been shown to have 25% of wild type activity and significantly reduced protein expression using fluorimetric and western blot assays on transfected HEK-293T cells (PMID: 19234632). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

Comment:

Variant summary: CYP1B1 c.182G>A (p.Gly61Glu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00032 in 198162 control chromosomes in the gnomAD database, including 2 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in CYP1B1 causing Primary Congenital Glaucoma (0.00032 vs 0.0043), allowing no conclusion about variant significance. c.182G>A has been reported in the literature in multiple individuals affected with Primary Congenital Glaucoma (Bejjani_1998). These data indicate that the variant is very likely to be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 9463332). ClinVar contains an entry for this variant (Variation ID: 7730). Based on the evidence outlined above, the variant was classified as pathogenic.

Comment:

The CYP1B1 c.182G>A variant is predicted to result in the amino acid substitution p.Gly61Glu. This variant in compound heterozygous and homozygous states has been reported to be causative for primary congenital glaucoma (PCG) (Bejjani et al. 1998. PubMed ID: 9463332; Abu-Amero et al. 2015. PubMed ID: 24099281; Micheal et al. 2015. PubMed ID: 25091052; Stoilov et al. 1998. PubMed ID: 9497261). This variant was seen in 78% of the PCG chromosomes analyzed and reported as a common variant in the Saudi Arabian population (Bejjani et al. 1998. PubMed ID: 9463332, reported as 3987G>A change). Functional studies have shown that this variant significantly reduces enzyme activity (Banerjee et al. 2016. PubMed ID: 27243976). This variant is reported in 0.041% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.

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
Primary Congenital Glaucoma.	Adam MP	-	2017	PMID: 20301314
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
CYP1B1 gene mutations with incomplete penetrance in a Chinese pedigree with primary congenital glaucoma: a case report and review of literatures.	Chen L	International journal of clinical and experimental medicine	2015	PMID: 26550445
Functional analysis of CYP1B1 mutations and association of heterozygous hypomorphic alleles with primary open-angle glaucoma.	López-Garrido MP	Clinical genetics	2010	PMID: 19793111
Variable expressivity and high penetrance of CYP1B1 mutations associated with primary congenital glaucoma.	Suri F	Ophthalmology	2009	PMID: 19744731
CYP1B1 mutations in Spanish patients with primary congenital glaucoma: phenotypic and functional variability.	Campos-Mollo E	Molecular vision	2009	PMID: 19234632
Mutations in CYP1B1 cause primary congenital glaucoma by reduction of either activity or abundance of the enzyme.	Chavarria-Soley G	Human mutation	2008	PMID: 18470941
Molecular basis of Peters anomaly in Saudi Arabia.	Edward D	Ophthalmic genetics	2004	PMID: 15621878
A novel frameshift founder mutation in the cytochrome P450 1B1 (CYP1B1) gene is associated with primary congenital glaucoma in Morocco.	Belmouden A	Clinical genetics	2002	PMID: 12372064
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
Mutations in CYP1B1, the gene for cytochrome P4501B1, are the predominant cause of primary congenital glaucoma in Saudi Arabia.	Bejjani BA	American journal of human genetics	1998	PMID: 9463332
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Text-mined citations for rs28936700 ...

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 Oct 20, 2024

ClinVar Genomic variation as it relates to human health

NM_000104.4(CYP1B1):c.182G>A (p.Gly61Glu)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs28936700 ...