ClinVar Genomic variation as it relates to human health
NM_207352.4(CYP4V2):c.992A>C (p.His331Pro)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_207352.4(CYP4V2):c.992A>C (p.His331Pro)
Variation ID: 39275 Accession: VCV000039275.15
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 4q35.2 4: 186205204 (GRCh38) [ NCBI UCSC ] 4: 187126358 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline May 3, 2013 Feb 14, 2024 Jan 11, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_207352.4:c.992A>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_997235.3:p.His331Pro missense NC_000004.12:g.186205204A>C NC_000004.11:g.187126358A>C NG_007965.1:g.18685A>C NG_012095.2:g.1226A>C LRG_565:g.1226A>C Q6ZWL3:p.His331Pro - Protein change
- H331P
- Other names
- c.1296A>C
- Canonical SPDI
- NC_000004.12:186205203:A:C
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00003
Exome Aggregation Consortium (ExAC) 0.00007
The Genome Aggregation Database (gnomAD), exomes 0.00008
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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CYP4V2 | - | - |
GRCh38 GRCh37 |
448 | 702 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (3) |
criteria provided, single submitter
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Aug 1, 2017 | RCV000032552.10 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jan 11, 2024 | RCV000490060.10 | |
Pathogenic (1) |
criteria provided, single submitter
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May 5, 2017 | RCV001074450.2 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Dec 24, 2018)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000577474.4
First in ClinVar: May 22, 2017 Last updated: Apr 17, 2019 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(May 05, 2017)
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criteria provided, single submitter
Method: clinical testing
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Retinal dystrophy
Affected status: yes
Allele origin:
germline
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Blueprint Genetics
Accession: SCV001240034.1
First in ClinVar: Apr 18, 2020 Last updated: Apr 18, 2020
Comment:
My Retina Tracker patient
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Pathogenic
(Jan 11, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001224645.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
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). … (more)
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. (less)
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Pathogenic
(Aug 01, 2017)
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criteria provided, single submitter
Method: clinical testing
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Bietti crystalline corneoretinal dystrophy
(Autosomal recessive inheritance)
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000731786.1
First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018 |
Comment:
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 … (more)
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. (less)
Number of individuals with the variant: 1
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Pathogenic
(Jun 01, 2005)
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no assertion criteria provided
Method: literature only
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BIETTI CRYSTALLINE CORNEORETINAL DYSTROPHY
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000246148.1
First in ClinVar: Sep 29, 2015 Last updated: Sep 29, 2015 |
Comment on evidence:
For discussion of the c.992A-C transversion in exon 8 of the CYP4V2 gene, resulting in a his331-to-pro (H331P) substitution, that was found in compound heterozygous … (more)
For discussion of the c.992A-C transversion in exon 8 of the CYP4V2 gene, resulting in a his331-to-pro (H331P) substitution, that was found in compound heterozygous state in Chinese patients with Bietti crystalline corneoretinal dystrophy (BCD; 210370) by Li et al. (2004) and Lin et al. (2005), see 608614.0006. (less)
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pathologic
(Apr 12, 2012)
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no assertion criteria provided
Method: curation
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Bietti Crystalline Dystrophy
Affected status: not provided
Allele origin:
not provided
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GeneReviews
Accession: SCV000056219.2
First in ClinVar: Apr 04, 2013 Last updated: May 03, 2013 |
Comment:
Converted during submission to Pathogenic.
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Bietti Crystalline Dystrophy. | Adam MP | - | 2019 | PMID: 22497028 |
PRPF3-Associated Autosomal Dominant Retinitis Pigmentosa and CYP4V2-Associated Bietti's Crystalline Corneoretinal Dystrophy Coexist in a Multigenerational Chinese Family. | Meng X | Journal of ophthalmology | 2017 | PMID: 28848678 |
Identification and population history of CYP4V2 mutations in patients with Bietti crystalline corneoretinal dystrophy. | Jiao X | European journal of human genetics : EJHG | 2017 | PMID: 28051075 |
Identification of CYP4V2 mutation in 36 Chinese families with Bietti crystalline corneoretinal dystrophy. | Yin X | Experimental eye research | 2016 | PMID: 26971461 |
Molecular genetic testing in clinical diagnostic assessments that demonstrate correlations in patients with autosomal recessive inherited retinal dystrophy. | Liu X | JAMA ophthalmology | 2015 | PMID: 25611614 |
Genotype-phenotype correlation and mutation spectrum in a large cohort of patients with inherited retinal dystrophy revealed by next-generation sequencing. | Huang XF | Genetics in medicine : official journal of the American College of Medical Genetics | 2015 | PMID: 25356976 |
Identification of novel CYP4V2 gene mutations in 92 Chinese families with Bietti's crystalline corneoretinal dystrophy. | Meng XH | Molecular vision | 2014 | PMID: 25593508 |
CYP4V2 in Bietti's crystalline dystrophy: ocular localization, metabolism of ω-3-polyunsaturated fatty acids, and functional deficit of the p.H331P variant. | Nakano M | Molecular pharmacology | 2012 | PMID: 22772592 |
Recessive mutations in the CYP4V2 gene in East Asian and Middle Eastern patients with Bietti crystalline corneoretinal dystrophy. | Lin J | Journal of medical genetics | 2005 | PMID: 15937078 |
Bietti crystalline corneoretinal dystrophy is caused by mutations in the novel gene CYP4V2. | Li A | American journal of human genetics | 2004 | PMID: 15042513 |
Text-mined citations for rs199476197 ...
HelpRecord last updated Sep 29, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.