rs199476197

chr4-186205204-A-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_207352.4(CYP4V2):c.992A>C(p.His331Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,614,076 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. H331H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

CYP4V2
NM_207352.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 8.70

Variant links:

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]

CYP4V2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.965

PP5

Variant 4-186205204-A-C is Pathogenic according to our data. Variant chr4-186205204-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 39275.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-186205204-A-C is described in Lovd as [Pathogenic]. Variant chr4-186205204-A-C is described in Lovd as [Pathogenic]. Variant chr4-186205204-A-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
CYP4V2	NM_207352.4 linkuse as main transcript	c.992A>C	p.His331Pro	missense_variant	8/11	ENST00000378802.5
CYP4V2	XM_005262935.5 linkuse as main transcript	c.992A>C	p.His331Pro	missense_variant	8/11
CYP4V2	XM_047450077.1 linkuse as main transcript	c.596A>C	p.His199Pro	missense_variant	6/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP4V2	ENST00000378802.5 linkuse as main transcript	c.992A>C	p.His331Pro	missense_variant	8/11	1	NM_207352.4	P1	Q6ZWL3-1
CYP4V2	ENST00000502665.1 linkuse as main transcript	n.227A>C		non_coding_transcript_exon_variant	2/5	1
CYP4V2	ENST00000507209.5 linkuse as main transcript	n.5690A>C		non_coding_transcript_exon_variant	3/6	1
CYP4V2	ENST00000513354.5 linkuse as main transcript	n.82A>C		non_coding_transcript_exon_variant	2/5	1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000755

AC:

AN:

251496

Hom.:

AF XY:

0.0000809

AC XY:

AN XY:

135922

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00103

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000137

AC:

AN:

1461844

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000504

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152232

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74370

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000192

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000192

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.0000741

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Bietti crystalline corneoretinal dystrophy

Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2005	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 01, 2017	The p.His331Pro (NM207352.3 c.992A>C) variant in CYP4V2 has been reported in at least 6 homozygous and 14 compound heterozygous individuals with Bietti crystall ine dystrophy and one family with retinitis pigmentosa (Huang 2015, Liu 2015, Yi n 2016, and Jiao 2017). In vitro functional studies on the p.His331Pro variant provide evidence supporting an impact on protein function (Nakano 2012). This va riant has been identified in 0.11% (19/17248) of East Asian chromosomes by the G enome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs19 9476197). Although this variant has been seen in the general population, its fre quency is low enough to be consistent with a recessive carrier frequency. In sum mary, this variant meets criteria to be classified as pathogenic for Bietti crys talline dystrophy in an autosomal recessive manner based upon its biallelic occu rrence in affected individuals and impact in functional studies. -
Pathogenic, no assertion criteria provided	curation	GeneReviews	Apr 12, 2012	- -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 11, 2024	This sequence change replaces histidine, which is basic and polar, with proline, which is neutral and non-polar, at codon 331 of the CYP4V2 protein (p.His331Pro). This variant is present in population databases (rs199476197, gnomAD 0.1%). This missense change has been observed in individual(s) with Bietti crystalline corneoretinal dystrophy (PMID: 15042513, 25611614, 26971461, 28848678). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 39275). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CYP4V2 protein function. Experimental studies have shown that this missense change affects CYP4V2 function (PMID: 22772592). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 24, 2018	The H331P variant in the CYP4V2 gene has been reported previously in association with Bietti crystalline corneoretinal dystrophy (BCD), and is seen in 7.4% of alleles in the Chinese population with BCD (Xiao et al., 2011; Huang et al., 2015; Yin et al., 2016). The H331P variant is observed in 19/17248 (0.11%) alleles from individuals of East Asian background, in large population cohorts (Lek et al., 2016). The H331P variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Functional studies show H331P has significantly lower steady-state protein expression levels compared to wild type and lipid profiling data are consistent with reduced metabolism of polyunsaturated fatty acids for the H331P variant (Nakano et al., 2012). We interpret H331P as a pathogenic variant. -

Retinal dystrophy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

May 05, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Uncertain

0.087

BayesDel_noAF

Pathogenic

0.30

Cadd

Pathogenic

Dann

Uncertain

0.99

DEOGEN2

Benign

0.35

Eigen

Pathogenic

0.90

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.97

M_CAP

Uncertain

0.18

MetaRNN

Pathogenic

0.97

MetaSVM

Uncertain

0.45

MutationAssessor

Pathogenic

4.7

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.72

PROVEAN

Pathogenic

-9.4

REVEL

Pathogenic

0.85

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.0030

Polyphen

1.0

Vest4

0.98

MutPred

0.90

Loss of catalytic residue at H331 (P = 0.0214);

MVP

0.96

MPC

0.50

ClinPred

0.95

GERP RS

5.5

Varity_R

0.98

gMVP

0.92

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over