Submissions for variant NM_000104.4(CYP1B1):c.868dup (p.Arg290fs)

dbSNP: rs587778875

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000363659	SCV000329328	pathogenic	not provided	2021-04-12	criteria provided, single submitter	clinical testing	Frameshift 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: 30820150, 24281366, 25091052, 17893647, 17591938, 25018621, 9097971, 25950505, 31589614)
Eurofins Ntd Llc (ga)	RCV000363659	SCV000859298	pathogenic	not provided	2018-02-07	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000778615	SCV000914927	pathogenic	CYP1B1-related disorder	2018-10-16	criteria provided, single submitter	clinical testing	The CYP1B1 c.868dupC (p.Arg290ProfsTer37) variant results in a frameshift and is predicted to result in premature termination of the protein. The p.Arg290ProfsTer37 variant has been reported in at least five studies and is found in a total of 11 individuals from six families including ten in a homozygous state and one in a compound heterozygous state (Stoilov et al. 1997; Bagiyeva et al. 2007; Micheal et al. 2014; Prokudin et al. 2014; Souzeau et al. 2015). The compound heterozygous proband presented with iris and fundal colobomas and micropthalmia. Of note, the proband's mildly affected brother did not have the p.Arg290ProfsTer37 variant and therefore the variant's contribution to disease is difficult to ascertain in this family (Prokudin et al. 2014). One affected homozygous individual presented with juvenile open-angle glaucoma, not primary congenital glaucoma (Souzeau et al. 2015). The p.Arg290ProfsTer37 variant was absent from 690 controls and is reported at a frequency of 0.00008 in the European (non-Finnish) population of the Exome Aggregation Consortium. Due to the potential impact of frameshift variants and the evidence in the literature, the p.Arg290ProfsTer37 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002228326	SCV000960002	pathogenic	Congenital glaucoma	2023-12-28	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg290Profs*37) 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 (rs587778875, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with primary congenital glaucoma or juvenile open angle glaucoma (PMID: 9097971, 17591938, 25091052, 25950505). It has also been observed to segregate with disease in related individuals. This variant is also known as c.862insC and single cytosine base insertion (nt 1209- 1214). ClinVar contains an entry for this variant (Variation ID: 68468). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV005003451	SCV002775712	pathogenic	Glaucoma 3A; Anterior segment dysgenesis 6	2024-04-20	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003466930	SCV004215464	pathogenic	Anterior segment dysgenesis 6	2024-02-25	criteria provided, single submitter	clinical testing
OMIM	RCV002279933	SCV000028373	pathogenic	Glaucoma 3A	1997-04-01	no assertion criteria provided	literature only
Eye Genetics Research Group, Children's Medical Research Institute	RCV000059339	SCV000087415	uncertain significance	Congenital ocular coloboma	2012-03-30	no assertion criteria provided	research
Institute of Basic Medical Sciences, Khyber Medical University, Peshawar	RCV002279933	SCV005088696	pathogenic	Glaucoma 3A	2023-12-06	no assertion criteria provided	research	A known frameshift homozygous mutation, c.868dupC was identified in CYP1B1 gene in Pakistani families. Later on, segregation studies also confirmed the mutation in other affected individuals in homozygous state while found in heterozygous pattern in parents and other normal siblings. All patients had uncontrollable IOP and bilateral corneal opacity with no perception of light. all the carriers of c.868dupC were phenotypically normal. Reference PMID: 30820150