NM_207352.4:c.802-8_810delTCATACAGGTCATCGCTinsGC

Variant names:

• chr4-186201149-TCATACAGGTCATCGCT-GC
• rs207482233
• NM_207352.4:c.802-8_810delTCATACAGGTCATCGCTinsGC

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_207352.4(CYP4V2):​c.802-8_810delTCATACAGGTCATCGCTinsGC​(p.Val268_Ala270del) variant causes a splice acceptor, conservative inframe deletion, splice region, synonymous, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. VI268?) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CYP4V2 NM_207352.4 splice_acceptor, conservative_inframe_deletion, splice_region, synonymous, intron
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:13
• Conservation: PhyloP100: 9.09

Genes affected

CYP4V2 (HGNC:23198): (cytochrome P450 family 4 subfamily V member 2) This gene encodes a member of the cytochrome P450 hemethiolate protein superfamily which are involved in oxidizing various substrates in the metabolic pathway. It is implicated in the metabolism of fatty acid precursors into n-3 polyunsaturated fatty acids. Mutations in this gene result in Bietti crystalline corneoretinal dystrophy. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.117870726 fraction of the gene. Cryptic splice site detected, with MaxEntScore 3.8, offset of -7, new splice context is: catgtgattatcattcaaAGcga. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 4-186201149-TCATACAGGTCATCGCT-GC is Pathogenic according to our data. Variant chr4-186201149-TCATACAGGTCATCGCT-GC is described in ClinVar as [Pathogenic]. Clinvar id is 39271.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP4V2	NM_207352.4	c.802-8_810delTCATACAGGTCATCGCTinsGC	p.Val268_Ala270del	splice_acceptor_variant, conservative_inframe_deletion, splice_region_variant, synonymous_variant, intron_variant	Exon 7 of 11	ENST00000378802.5	NP_997235.3
CYP4V2	XM_005262935.5	c.802-8_810delTCATACAGGTCATCGCTinsGC	p.Val268_Ala270del	splice_acceptor_variant, conservative_inframe_deletion, splice_region_variant, synonymous_variant, intron_variant	Exon 7 of 11		XP_005262992.1
CYP4V2	XM_047450077.1	c.406-8_414delTCATACAGGTCATCGCTinsGC	p.Val136_Ala138del	splice_acceptor_variant, conservative_inframe_deletion, splice_region_variant, synonymous_variant, intron_variant	Exon 5 of 9		XP_047306033.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP4V2	ENST00000378802.5	c.802-8_810delTCATACAGGTCATCGCTinsGC	p.Val268_Ala270del	splice_acceptor_variant, conservative_inframe_deletion, splice_region_variant, synonymous_variant, intron_variant	Exon 7 of 11	1	NM_207352.4	ENSP00000368079.4
CYP4V2	ENST00000507209.5	n.1643-8_1651delTCATACAGGTCATCGCTinsGC		splice_acceptor_variant, splice_region_variant, intron_variant, non_coding_transcript_exon_variant	Exon 3 of 6	1

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Bietti crystalline corneoretinal dystrophy Pathogenic:9

Apr 08, 2021

Ocular Genomics Institute, Massachusetts Eye and Ear

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

The CYP4V2 c.802-8_810delinsGC 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: PM2, PVS1, PM3. Based on this evidence we have classified this variant as Pathogenic. -

Feb 05, 2020

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 12, 2012

GeneReviews

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: curation

- -

-

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1_Strong+PM3_VeryStrong -

Feb 05, 2025

SingHealth Duke-NUS Institute of Precision Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant is predicted to cause LOF through truncating >10% of the protein, in a gene where LOF is a known cause of pathogenicity (PVS1). Variant is not found in gnomAD genomes and exomes (PM2). Cosegregation with disease phenotype is observed in multiple families within the cohort (PP1) -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.802-8_810delTCATACAGGTCATCGCTinsGC variant, also described in the literature as c.802-8_810delinsG, occurs in a canonical splice site (acceptor) and is therefore predicted to disrupt or distort the normal gene product. The c.802-8_810delTCATACAGGTCATCGCTinsGC variant is the most common variant associated with Bietti crystalline dystrophy in the Japanese and Chinese populations, accounting for up to 83% of disease alleles (Park et al. 2016). The variant has been reported in at least nine studies in which it is found in at least 130 patients including 64 in a homozygous state, 65 in a compound heterozygous state and one individual in a heterozygous state in whom a second allele has not been detected (Li et al. 2004; Wada et al. 2006; Lai et al. 2007; Xiao et al. 2011; Yin et al. 2014; Meng et al. 2014; Tian et al. 2015; Park et al. 2016; Astuti et al. 2016). The variant was absent from 146 controls but is reported at a frequency of 0.00496 in the East Asian population of the 1000 Genomes Project. Due to the potential impact of splice acceptor variants and the supporting evidence from the literature, the c.802-8_810delTCATACAGGTCATCGCTinsGC variant is classified as pathogenic for Bietti crystalline dystrophy. -

-

Department of Ophthalmology and Visual Sciences Kyoto University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Feb 06, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.802-8_810delinsGC (NM_207352.3 c.802-8_810delinsGC) variant in CYP4V2 has been reported in over 60 homozygous and compound heterozygous individuals with B ietti crystalline dystrophy and related disorders and is the most common variant associated with this disease in East Asian populations (Wada 2005, Lin 2005, La i 2007, Yokoi 2010, Xiao 2011, Wang 2012, Chung 2013, Fu 2013, Yin 2014, Meng 20 14, Tian 2015, Astuti 2015, and Park 2016). This variant has also been reported as pathogenic in ClinVar (Variation ID#39271). This variant has been identified in 0.2% (16/8520) of East Asian chromosomes by chromosomes by the Exome Aggregat ion Consortium (ExAC, http://exac.broadinstitute.org). This variant alters the c anonical splice site, and therefore is expected to impact splicing and lead to a n absent or truncated protein. In summary, this variant meets criteria to be cla ssified as pathogenic for Bietti crystalline dystrophy and related disorders in an autosomal recessive manner based upon its biallelic occurrence in patients wi th this disease and predicted functional impact. -

Jun 14, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:2

Nov 18, 2016

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 14, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown.; Reported as the most common pathogenic variant among individuals of East Asian background, accounting for 62.6% of pathogenic variants identified in one study (Zhang et al., 2018); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27658286, 25629076, 15042513, 23793346, 22693542, 15860296, 26865810, 24480711, 28848678, 16088246, 28763560, 30029497, 19508456, 30609409, 31054281, 31872526, 31960602, 33964374, 33857831, 33090715, 33306817, 33781268, 34068831, 30429639, 15937078) -

Retinal dystrophy Pathogenic:2

Apr 23, 2019

Blueprint Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 01, 2017

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs207482233; hg19: chr4-187122303;