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

gnomAD frequency: 0.00022  dbSNP: rs72549387

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000169657	SCV000221185	pathogenic	Glaucoma 3A	2013-11-26	criteria provided, single submitter	clinical testing	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.
Illumina Laboratory Services, Illumina	RCV000331073	SCV000430286	pathogenic	CYP1B1-related disorder	2017-04-28	criteria provided, single submitter	clinical testing	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.
GeneDx	RCV000489919	SCV000576811	pathogenic	not provided	2023-01-10	criteria provided, single submitter	clinical testing	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)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000692947	SCV000820798	pathogenic	Congenital glaucoma	2024-11-27	criteria provided, single submitter	clinical testing	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.
Fulgent Genetics, Fulgent Genetics	RCV000763084	SCV000893610	pathogenic	Glaucoma 3A; Glaucoma 3, primary infantile, B; Anterior segment dysgenesis 6	2018-10-31	criteria provided, single submitter	clinical testing
Genomics England Pilot Project, Genomics England	RCV000169657	SCV001760088	pathogenic	Glaucoma 3A		criteria provided, single submitter	clinical testing
Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota	RCV000416316	SCV001981539	pathogenic	Anterior segment dysgenesis 6	2021-08-25	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000489919	SCV002024010	likely pathogenic	not provided	2020-12-16	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000416316	SCV004215451	pathogenic	Anterior segment dysgenesis 6	2024-03-27	criteria provided, single submitter	clinical testing
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000489919	SCV005197680	pathogenic	not provided	2022-05-27	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005025028	SCV005663697	pathogenic	Glaucoma 3A; Anterior segment dysgenesis 6	2024-04-10	criteria provided, single submitter	clinical testing
OMIM	RCV000416316	SCV000028381	pathogenic	Anterior segment dysgenesis 6	2001-05-01	no assertion criteria provided	literature only
Eye Genetics Research Group, Children's Medical Research Institute	RCV000008176	SCV000087413	pathogenic	Irido-corneo-trabecular dysgenesis	2012-03-30	no assertion criteria provided	research
Eye Genetics Research Group, Children's Medical Research Institute	RCV001200036	SCV001370528	pathogenic	Anterior segment dysgenesis	2020-03-31	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000331073	SCV004121223	pathogenic	CYP1B1-related disorder	2024-01-17	no assertion criteria provided	clinical testing	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.