Submissions for variant NM_000104.4(CYP1B1):c.535del (p.Ala179fs)

dbSNP: rs771076928

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000627426	SCV000748424	pathogenic	not provided	2018-04-23	criteria provided, single submitter	clinical testing	The c.535delG variant in the CYP1B1 gene has been reported previously in association with autosomal recessive primary congenital glaucoma, and has been reported as a founder mutation in the Moroccan population (Belmouden et al., 2002; Gronskov et al., 2016). This variant causes a frameshift starting with codon Alanine 179, changes this amino acid to an Arginine residue, and creates a premature Stop codon at position 18 of the new reading frame, denoted p.Ala179ArgfsX18. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.535delG variant is observed in 4/26120 (0.015%) alleles from individuals of Latino background and 7/182840 (0.004%) global alleles in large population cohorts, with no homozygotes identified (Lek et al., 2016). We interpret c.535delG as a pathogenic variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000631367	SCV000752402	pathogenic	Congenital glaucoma	2024-11-11	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ala179Argfs*18) 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 (rs771076928, gnomAD 0.02%). This premature translational stop signal has been observed in individuals with open-angle glaucoma, and primary congenital glaucoma (PMID: 12372064, 19234632, 23922489, 27272408, 27777502, 27820421). It has also been observed to segregate with disease in related individuals. This variant is also known as c.4339delG, c.906delG, c.534_535delG (p.Ala179ArgfsX16). ClinVar contains an entry for this variant (Variation ID: 523943). For these reasons, this variant has been classified as Pathogenic.
3billion, Medical Genetics	RCV001250447	SCV002058588	pathogenic	Glaucoma 3A	2022-01-03	criteria provided, single submitter	clinical testing	Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000048, PM2_M). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000523943, PMID:12372064).Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Fulgent Genetics, Fulgent Genetics	RCV002491346	SCV002792131	pathogenic	Glaucoma 3A; Glaucoma 3, primary infantile, B; Anterior segment dysgenesis 6	2021-08-30	criteria provided, single submitter	clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV001250447	SCV003806852	pathogenic	Glaucoma 3A	2023-01-31	criteria provided, single submitter	clinical testing	ACMG classification criteria: PVS1 very strong, PM2 supporting, PM3 strong
PreventionGenetics, part of Exact Sciences	RCV004533300	SCV004113890	pathogenic	CYP1B1-related disorder	2023-06-07	criteria provided, single submitter	clinical testing	The CYP1B1 c.535delG variant is predicted to result in a frameshift and premature protein termination (p.Ala179Argfs*18). This variant was reported in the homozygous or compound heterozygous state to be causative for primary congenital glaucoma (described as 4339delG, Bouyacoub et al. 2014. PubMed ID: 24942078; Cardoso et al. 2015. PubMed ID: 25952714; García-Antón et al. 2017. PubMed ID: 28448622). This variant is reported in 0.019% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-38301996-GC-G). Frameshift variants in CYP1B1 are expected to be pathogenic. This variant is interpreted as pathogenic.
Baylor Genetics	RCV001449669	SCV004215462	pathogenic	Anterior segment dysgenesis 6	2024-03-20	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000627426	SCV004235472	pathogenic	not provided	2023-06-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004782478	SCV005395037	pathogenic	Primary congenital glaucoma	2024-09-10	criteria provided, single submitter	clinical testing	Variant summary: CYP1B1 c.535delG (p.Ala179ArgfsX18) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 5.1e-05 in 156224 control chromosomes (gnomAD). c.535delG has been reported in the literature in at least an individual affected with Primary Congenital Glaucoma (example: Reis_2016). These data indicate that the variant may be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 27272408). ClinVar contains an entry for this variant (Variation ID: 523943). Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM	RCV001250447	SCV000028382	pathogenic	Glaucoma 3A	2002-10-01	no assertion criteria provided	literature only
Institute of Medical Molecular Genetics, University of Zurich	RCV001250447	SCV001424835	pathogenic	Glaucoma 3A	2019-08-01	no assertion criteria provided	research
OMIM	RCV001449669	SCV001652918	pathogenic	Anterior segment dysgenesis 6	2002-10-01	no assertion criteria provided	literature only