Submissions for variant NM_000104.4(CYP1B1):c.1064_1076del (p.Arg355fs)

gnomAD frequency: 0.00024  dbSNP: rs72549380

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000260225	SCV000334096	pathogenic	not provided	2015-08-31	criteria provided, single submitter	clinical testing
Invitae	RCV000695529	SCV000824035	pathogenic	Congenital glaucoma	2024-01-29	criteria provided, single submitter	clinical testing	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.
GeneDx	RCV000260225	SCV001167841	pathogenic	not provided	2023-09-19	criteria provided, single submitter	clinical testing	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)
CeGaT Center for Human Genetics Tuebingen	RCV000260225	SCV001247369	pathogenic	not provided	2016-12-01	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001250446	SCV001369133	pathogenic	Glaucoma 3A	2019-05-31	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1.
Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota	RCV001730655	SCV001981540	pathogenic	Anterior segment dysgenesis 6	2021-08-25	criteria provided, single submitter	clinical testing
3billion	RCV001250446	SCV002058821	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 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.
Genetics and Molecular Pathology, SA Pathology	RCV001250446	SCV002556849	pathogenic	Glaucoma 3A	2021-10-11	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002503986	SCV002811608	pathogenic	Glaucoma 3A; Glaucoma 3, primary infantile, B; Anterior segment dysgenesis 6	2022-03-21	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004535284	SCV004115113	pathogenic	CYP1B1-related disorder	2022-08-24	criteria provided, single submitter	clinical testing	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.
Baylor Genetics	RCV001730655	SCV004215448	pathogenic	Anterior segment dysgenesis 6	2023-10-28	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV001250446	SCV004847302	pathogenic	Glaucoma 3A	2023-07-28	criteria provided, single submitter	clinical testing	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
OMIM	RCV001250446	SCV000028372	pathogenic	Glaucoma 3A	1997-04-01	no assertion criteria provided	literature only
Institute of Medical Molecular Genetics, University of Zurich	RCV001250446	SCV001424834	pathogenic	Glaucoma 3A	2019-08-01	no assertion criteria provided	research