VCV000039264.48 - ClinVar

NM_207352.4(CYP4V2):c.367A>G (p.Met123Val)

Germline

Classification

criteria provided, conflicting classifications. Learn more about how ClinVar calculates review status.

Conflicting classifications of pathogenicity
Likely pathogenic(1); Uncertain significance(6); Benign(1)

8 out of 10 submissions contributed to this classification

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.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_207352.4(CYP4V2):c.367A>G (p.Met123Val)

Variation ID: 39264 Accession: VCV000039264.48

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 4q35.1 4: 186196042 (GRCh38) [ NCBI UCSC ] 4: 187117196 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	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	Jun 8, 2025	Oct 30, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_207352.4:c.367A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_997235.3:p.Met123Val	missense
NC_000004.12:g.186196042A>G
NC_000004.11:g.187117196A>G
NG_007965.1:g.9523A>G
	Q6ZWL3:p.Met123Val

... more HGVS ... less HGVS

Protein change

M123V

Other names

c.671A>G

Canonical SPDI

NC_000004.12:186196041:A:G

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

0.00120 (G)

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD) 0.00027

Trans-Omics for Precision Medicine (TOPMed) 0.00048

The Genome Aggregation Database (gnomAD), exomes 0.00079

1000 Genomes Project 30x 0.00094

The Genome Aggregation Database (gnomAD) 0.00021

Exome Aggregation Consortium (ExAC) 0.00070

1000 Genomes Project 0.00120

Links

ClinGen: CA232864 UniProtKB: Q6ZWL3#VAR_023088 dbSNP: rs149684063 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help 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.
CYP4V2		Gene associated with autosomal recessive phenotype	Not yet evaluated	GRCh38 GRCh37	481	740

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help 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 Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Bietti crystalline corneoretinal dystrophy	Uncertain significance (3)	criteria provided, multiple submitters, no conflicts	Sep 1, 2022	RCV000032541.14
not provided	Conflicting classifications of pathogenicity (3)	criteria provided, conflicting classifications	Oct 30, 2024	RCV000132718.38
Corneal dystrophy	Uncertain significance (1)	criteria provided, single submitter	Apr 27, 2017	RCV000260520.6
Retinal dystrophy	Conflicting classifications of pathogenicity (3)	criteria provided, conflicting classifications	Oct 1, 2023	RCV001074793.6

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 Help 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 Help 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.
Uncertain significance (Mar 18, 2016) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: reference population	Bietti crystalline corneoretinal dystrophy Affected status: unknown Allele origin: germline	Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center Accession: SCV000267285.1 First in ClinVar: May 24, 2017 Last updated: May 24, 2017	Publications: PubMed (1) PubMed: 15042513 Number of individuals with the variant: 1 Age: 40-69 years Ethnicity/Population group: East Asian Geographic origin: South Korean

Uncertain significance (Jul 03, 2019) C Contributing to aggregate classification	criteria provided, single submitter (Blueprint Genetics Variant Classification Scheme) Method: clinical testing	Retinal dystrophy Affected status: yes Allele origin: germline	Blueprint Genetics Accession: SCV001240390.1 First in ClinVar: Apr 18, 2020 Last updated: Apr 18, 2020 Comment: My Retina Tracker patient

Uncertain significance (Apr 27, 2017) C Contributing to aggregate classification	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Corneal dystrophy Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000448828.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)

Uncertain significance (Sep 01, 2022) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Bietti crystalline corneoretinal dystrophy Affected status: yes Allele origin: germline	3billion Accession: SCV002572707.1 First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022	Publications: PubMed (1) PubMed: 15042513 Comment: The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.074%). Same nucleotide change resulting in same amino … (more) The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.074%). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with CYP4V2-related disorder (PMID: 15042513). However, the evidence of pathogenicity is insufficient at this time. Therefore, this variant is classified as uncertain significance according to the recommendation of ACMG/AMP guideline. (less) Clinical Features: Exudative vitreoretinopathy (present) Zygosity: Single Heterozygote

Likely pathogenic (Oct 01, 2023) C Contributing to aggregate classification	criteria provided, single submitter (Submitter's publication) Method: research	Retinal dystrophy Affected status: yes Allele origin: germline	Dept Of Ophthalmology, Nagoya University Accession: SCV004706578.1 First in ClinVar: Mar 10, 2024 Last updated: Mar 10, 2024

Uncertain significance (Jan 01, 2017) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Retinal dystrophy Affected status: yes Allele origin: germline	Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg Accession: SCV005072011.1 First in ClinVar: Dec 28, 2024 Last updated: Dec 28, 2024	Publications: PubMed (7) PubMed: 15042513‚ 28453600‚ 31872526‚ 33090715‚ 34923510‚ 34426522‚ 33816482

Benign (Oct 30, 2024) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001733227.5 First in ClinVar: Jun 15, 2021 Last updated: Feb 25, 2025

Uncertain significance (Aug 01, 2019) C Contributing to aggregate classification	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001249265.30 First in ClinVar: May 12, 2020 Last updated: May 25, 2025	Number of individuals with the variant: 1

Likely benign (-) N Not contributing to aggregate classification	no assertion criteria provided Method: not provided	not provided Affected status: not provided Allele origin: unknown	Department of Ophthalmology and Visual Sciences Kyoto University Accession: SCV000172672.2 First in ClinVar: Aug 08, 2014 Last updated: Jun 08, 2025	Comment: Converted during submission from probable-non-pathogenic to Likely benign.

Pathogenic (Apr 12, 2012) N Not contributing to aggregate classification	no assertion criteria provided Method: curation	Bietti Crystalline Dystrophy Affected status: not provided Allele origin: unknown	GeneReviews Accession: SCV000056208.3 First in ClinVar: Apr 04, 2013 Last updated: Jun 08, 2025	Comment: Converted during submission from pathologic to Pathogenic.

Comment:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

Comment:

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.074%). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with CYP4V2-related disorder (PMID: 15042513). However, the evidence of pathogenicity is insufficient at this time. Therefore, this variant is classified as uncertain significance according to the recommendation of ACMG/AMP guideline.

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.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
PREDICTED PROTEIN STRUCTURE VARIATIONS INDICATE THE CLINICAL PRESENTATION OF CYP4V2-RELATED BIETTI CRYSTALLINE DYSTROPHY.	Chan LW	Retina (Philadelphia, Pa.)	2022	PMID: 34923510
The genetic structure of the Turkish population reveals high levels of variation and admixture.	Kars ME	Proceedings of the National Academy of Sciences of the United States of America	2021	PMID: 34426522
Evaluation of the Genetic Variation Spectrum Related to Corneal Dystrophy in a Large Cohort.	Li W	Frontiers in cell and developmental biology	2021	PMID: 33816482
Molecular diagnosis based on comprehensive genetic testing in 800 Chinese families with non-syndromic inherited retinal dystrophies.	Liu X	Clinical & experimental ophthalmology	2021	PMID: 33090715
Mutation spectrum and genotype-phenotype correlation of inherited retinal dystrophy in Taiwan.	Chen ZJ	Clinical & experimental ophthalmology	2020	PMID: 31872526
Bietti Crystalline Dystrophy.	Adam MP	-	2019	PMID: 22497028
Whole Exome Sequencing in Eight Thai Patients With Leber Congenital Amaurosis Reveals Mutations in the CTNNA1 and CYP4V2 Genes.	Jinda W	Investigative ophthalmology & visual science	2017	PMID: 28453600
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 rs149684063 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Jun 08, 2025

ClinVar Genomic variation as it relates to human health

NM_207352.4(CYP4V2):c.367A>G (p.Met123Val)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs149684063 ...