Submissions for variant NM_207352.4(CYP4V2):c.1091-2A>G

gnomAD frequency: 0.00001  dbSNP: rs199476183

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000002275	SCV000448857	pathogenic	Bietti crystalline corneoretinal dystrophy	2017-04-27	criteria provided, single submitter	clinical testing	The CYP4V2 c.1091-2A>G variant occurs in a canonical splice site (acceptor) and is therefore predicted to disrupt or distort the normal gene product. Across a selection of available literature, the c.1091-2A>G variant has been identified in 30 individuals with retinal atrophy, Bietti crystalline dystrophy, or retinitis pigmentosa, including in a homozygous state in five individuals and in a compound heterozygous state in 25 individuals. In addition, it was reported in a heterozygous state in five unaffected family members (Li et al. 2004; Xiao et al. 2011; Wang et al. 2012; Fu et al. 2013; Meng et al. 2014). The c.1091-2A>G variant was absent from 196 controls and is reported at a frequency of 0.00035 in the East Asian population of the Exome Aggregation Consortium. Based on the potential impact of splice acceptor variants and evidence from the literature, the c.1091-2A>G variant is classified as pathogenic for Bietti crystalline dystrophy. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Ocular Genomics Institute, Massachusetts Eye and Ear	RCV000002275	SCV001573350	pathogenic	Bietti crystalline corneoretinal dystrophy	2021-04-08	criteria provided, single submitter	research	The CYP4V2 c.1091-2A>G variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PVS1, PM2, PM3. Based on this evidence we have classified this variant as Pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001851576	SCV002229249	pathogenic	not provided	2024-10-21	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 8 of the CYP4V2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CYP4V2 are known to be pathogenic (PMID: 15042513, 25118264). This variant is present in population databases (rs199476183, gnomAD 0.06%). Disruption of this splice site has been observed in individual(s) with Bietti crystalline dystrophy and retinitis pigmentosa (PMID: 15042513). This variant is also known as IVS8-2A>G. ClinVar contains an entry for this variant (Variation ID: 2191). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Dept Of Ophthalmology, Nagoya University	RCV003887849	SCV004706595	likely pathogenic	Retinal dystrophy	2023-10-01	criteria provided, single submitter	research
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV000002275	SCV005417748	pathogenic	Bietti crystalline corneoretinal dystrophy		criteria provided, single submitter	clinical testing	PVS1_Strong+PM3_VeryStrong+PP1_Strong+PP4+PM2_Supporting
SingHealth Duke-NUS Institute of Precision Medicine	RCV000002275	SCV005881610	likely pathogenic	Bietti crystalline corneoretinal dystrophy	2025-02-05	criteria provided, single submitter	clinical testing	Variant is predicted to cause LOF through splicing in a gene where LOF is a known cause of pathogenicity (PVS1). Variant is not found in gnomAD genomes and homozygous allele count in gnomAD exomes are less than 0 (PM2).
OMIM	RCV000002275	SCV000022433	pathogenic	Bietti crystalline corneoretinal dystrophy	2013-06-14	no assertion criteria provided	literature only
GeneReviews	RCV000002275	SCV000058224	pathogenic	Bietti crystalline corneoretinal dystrophy	2012-04-12	no assertion criteria provided	curation	Converted during submission from pathologic to Pathogenic.