VCV001341163.1 - ClinVar

GRCh37/hg19 4p16.3(chr4:68345-1675143)x1

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.

(1)

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

no assertion criteria provided

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

GRCh37/hg19 4p16.3(chr4:68345-1675143)x1

Variation ID: 1341163 Accession: VCV001341163.1

Type and length

copy number loss, 1,606,799 bp

Location

Cytogenetic: 4p16.3 4: 68345-1675143 (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	Feb 13, 2022	Feb 13, 2022	Feb 1, 2021

HGVS

Nucleotide	Protein	Molecular consequence
NC_000004.11:g.(?_68345)_(1675143_?)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.
FGFRL1		No evidence available	No evidence available	GRCh38 GRCh37	293	451
ATP5ME		-	-	GRCh38 GRCh37	9	170
CPLX1		-	-	GRCh38 GRCh37	72	230
CRIPAK		-	-	GRCh38 GRCh37	-	288
CTBP1		-	-	GRCh38 GRCh37	112	433
DGKQ		-	-	GRCh38 GRCh37	130	293
FAM53A		-	-	GRCh38 GRCh38 GRCh37	70	221
GAK		-	-	GRCh38 GRCh37	118	314
IDUA		-	-	GRCh38 GRCh37	1419	2299
MAEA		-	-	GRCh38 GRCh37	17	172

There are 16 more genes affected by this variant. See the full set of genes in Variation Viewer (GRCh37) and ClinGen Dosage Sensitivity Map.

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.
not provided	Pathogenic (1)	no assertion criteria provided	Feb 1, 2021	RCV001834475.1

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 (Feb 01, 2021)	no assertion criteria provided Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Quest Diagnostics Nichols Institute San Juan Capistrano Accession: SCV002095739.1 First in ClinVar: Feb 13, 2022 Last updated: Feb 13, 2022	Comment: This terminal deletion of 4p16.3 is associated with Wolf-Hirschhorn syndrome (WHS), a contiguous gene deletion syndrome associated with a hemizygous deletion of chromosome 4p16.3 (OMIM … (more) This terminal deletion of 4p16.3 is associated with Wolf-Hirschhorn syndrome (WHS), a contiguous gene deletion syndrome associated with a hemizygous deletion of chromosome 4p16.3 (OMIM #194190). It is characterized by typical craniofacial features in infancy consisting of "Greek warrior helmet" appearance of the nose, microcephaly, high anterior hairline with prominent glabella, widely spaced eyes, epicanthus, highly arched eyebrows, short philtrum, downturned corners of the mouth, micrognathia, and poorly formed ears with pits/tags. All affected individuals have prenatal-onset growth deficiency followed by postnatal growth retardation and hypotonia with muscle underdevelopment. Developmental delay/intellectual disability of variable degree is present in all. Seizures occur in 90% to 100% of children with WHS. Other findings include skeletal anomalies (60%-70%), congenital heart defects (~50%), hearing loss (mostly conductive) (>40%), urinary tract malformations (25%), and structural brain abnormalities (33%). Although WHSC1/NSD2 and LETM1 are typically deleted in WHS, deletion of additional genes is likely required for the full expression of the phenotype. About 40%-45% have an unbalanced translocation with both a deletion of 4p and a partial trisomy of a different chromosome arm. These unbalanced translocations may be de novo or inherited from a parent with a balanced rearrangement. (Battaglia et al., GeneReviews. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1183/; Paradowska-Stolarz Adv Clin Exp Med. 2014 May-Jun;23(3):485-9. PMID: 24979523). (less)

Comment:

This terminal deletion of 4p16.3 is associated with Wolf-Hirschhorn syndrome (WHS), a contiguous gene deletion syndrome associated with a hemizygous deletion of chromosome 4p16.3 (OMIM #194190). It is characterized by typical craniofacial features in infancy consisting of "Greek warrior helmet" appearance of the nose, microcephaly, high anterior hairline with prominent glabella, widely spaced eyes, epicanthus, highly arched eyebrows, short philtrum, downturned corners of the mouth, micrognathia, and poorly formed ears with pits/tags. All affected individuals have prenatal-onset growth deficiency followed by postnatal growth retardation and hypotonia with muscle underdevelopment. Developmental delay/intellectual disability of variable degree is present in all. Seizures occur in 90% to 100% of children with WHS. Other findings include skeletal anomalies (60%-70%), congenital heart defects (~50%), hearing loss (mostly conductive) (>40%), urinary tract malformations (25%), and structural brain abnormalities (33%). Although WHSC1/NSD2 and LETM1 are typically deleted in WHS, deletion of additional genes is likely required for the full expression of the phenotype. About 40%-45% have an unbalanced translocation with both a deletion of 4p and a partial trisomy of a different chromosome arm. These unbalanced translocations may be de novo or inherited from a parent with a balanced rearrangement. (Battaglia et al., GeneReviews. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1183/; Paradowska-Stolarz Adv Clin Exp Med. 2014 May-Jun;23(3):485-9. PMID: 24979523).

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

There are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar.

Text-mined citations for this variant ...

Record last updated May 17, 2022

ClinVar Genomic variation as it relates to human health

GRCh37/hg19 4p16.3(chr4:68345-1675143)x1

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...