VCV001374349.6 - ClinVar

NC_000004.11:g.(?_186064527)_(187630981_?)del

Germline

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.

(2)

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.

Pathogenic

criteria provided, single submitter

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NC_000004.11:g.(?_186064527)_(187630981_?)del

Variation ID: 1374349 Accession: VCV001374349.6

Type and length

Deletion, 1,566,455 bp

Location

Cytogenetic: 4q35.1-35.2 4: 186064527-187630981 (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	Mar 28, 2022	Nov 11, 2023	Jul 19, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NC_000004.11:g.(?_186064527)_(187630981_?)del

Protein change

Other names

Canonical SPDI

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.

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

Links

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.
ANKRD37		-	-	GRCh38 GRCh37	-	143
CCDC110		-	-	GRCh38 GRCh37	44	186
CFAP96	-	-	-	GRCh38 GRCh37	5	163
CFAP97		-	-	GRCh38 GRCh37	54	184
CYP4V2		-	-	GRCh38 GRCh37	449	703
F11		-	-	GRCh38 GRCh37	501	818
FAM149A	-	-	-	GRCh38 GRCh37	58	195
FAT1		-	-	GRCh38 GRCh37	1046	1389
KLKB1		-	-	GRCh38 GRCh37	109	334
LRP2BP		-	-	GRCh38 GRCh37	-	154

There are 7 more genes affected by this variant. See the full set of genes in Variation Viewer (GRCh37).

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.
Herpes simplex encephalitis, susceptibility to, 1	no classifications from unflagged records (1)	no classifications from unflagged records	-	RCV001877781.7
not provided	Pathogenic (1)	criteria provided, single submitter	Jul 19, 2022	RCV003120734.4

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.
Pathogenic (Jul 19, 2022)	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: SCV003795415.2 First in ClinVar: Feb 13, 2023 Last updated: Nov 11, 2023	Publications: PubMed (3) PubMed: 15042513‚ 25118264‚ 25629076 Comment: A gross deletion of the genomic region encompassing the full coding sequence of the CYP4V2 gene has been identified. Loss-of-function variants in CYP4V2 are known … (more) A gross deletion of the genomic region encompassing the full coding sequence of the CYP4V2 gene has been identified. Loss-of-function variants in CYP4V2 are known to be pathogenic (PMID: 15042513, 25118264). The boundaries of this event are unknown as they extend beyond the assayed region for this gene and therefore may encompass additional genes. Isolated whole-gene deletions of CYP4V2 have not been reported in the literature. However, larger copy number events that include this gene have been reported (PMID: 25629076). For these reasons, this variant has been classified as Pathogenic. (less)
Uncertain significance (Nov 01, 2022)	Flagged submission flagged submission (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing Reason: This record appears to be redundant with a more recent record from the same submitter. Notes: SCV002139384 appears to (...more) Source: NCBI	Herpes simplex encephalitis, susceptibility to, 1 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002139384.3 First in ClinVar: Mar 28, 2022 Last updated: Nov 11, 2023	Comment: A gross deletion of the genomic region encompassing the full coding sequence of the TLR3 gene has been identified. The current clinical and genetic evidence … (more) A gross deletion of the genomic region encompassing the full coding sequence of the TLR3 gene has been identified. The current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in TLR3 cause disease. The boundaries of this event are unknown as they extend beyond the assayed region for this gene and therefore may encompass additional genes. This variant has not been reported in the literature in individuals affected with TLR3-related conditions. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more

Comment:

A gross deletion of the genomic region encompassing the full coding sequence of the CYP4V2 gene has been identified. Loss-of-function variants in CYP4V2 are known to be pathogenic (PMID: 15042513, 25118264). The boundaries of this event are unknown as they extend beyond the assayed region for this gene and therefore may encompass additional genes. Isolated whole-gene deletions of CYP4V2 have not been reported in the literature. However, larger copy number events that include this gene have been reported (PMID: 25629076). For these reasons, this variant has been classified as Pathogenic.

Comment:

A gross deletion of the genomic region encompassing the full coding sequence of the TLR3 gene has been identified. The current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in TLR3 cause disease. The boundaries of this event are unknown as they extend beyond the assayed region for this gene and therefore may encompass additional genes. This variant has not been reported in the literature in individuals affected with TLR3-related conditions. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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
Novel insights into the molecular pathogenesis of CYP4V2-associated Bietti's retinal dystrophy.	Astuti GD	Molecular genetics & genomic medicine	2015	PMID: 25629076
Generation and characterization of a murine model of Bietti crystalline dystrophy.	Lockhart CM	Investigative ophthalmology & visual science	2014	PMID: 25118264
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 this variant ...

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NC_000004.11:g.(?_186064527)_(187630981_?)del

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...