VCV000031110.1 - ClinVar

NM_018699.3(PRDM5):c.946_1623del

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

NM_018699.3(PRDM5):c.946_1623del

Variation ID: 31110 Accession: VCV000031110.1

Type and length

Deletion, -

Location

Cytogenetic: 4q27 -

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	Jun 7, 2018	Jun 7, 2018	Jun 10, 2011

HGVS

Protein change

Other names

52.46-KB DEL

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

OMIM: 614161.0001

Comment on variant

The presence of exons 1–8 and 15 and 16 was shown by PCR, but no genomic sequencing was given in PMID 21664999; the deleted region was defined by nullzygosity analysis for 34 adjacent SNPs within the autozygous region.

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.
PRDM5		-	-	GRCh38 GRCh37	663	691

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.
Brittle cornea syndrome 2	Pathogenic (1)	no assertion criteria provided	Jun 10, 2011	RCV000024106.5

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 (Jun 10, 2011)	no assertion criteria provided Method: literature only	BRITTLE CORNEA SYNDROME 2 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000045397.3 First in ClinVar: Apr 04, 2013 Last updated: Jun 07, 2018	Publications: PubMed (2) PubMed: 21664999‚ 26395458 Comment on evidence: In 4 affected members of a consanguineous Pakistani family with brittle cornea syndrome-2 (BCS2; 614170), Burkitt Wright et al. (2011) identified homozygosity for a 52.46-kb … (more) In 4 affected members of a consanguineous Pakistani family with brittle cornea syndrome-2 (BCS2; 614170), Burkitt Wright et al. (2011) identified homozygosity for a 52.46-kb in-frame deletion encompassing exons 9 through 14 of the PRDM5 gene, predicted to result in the loss of zinc fingers 6 through 13 of the protein. The deletion was not found in 454 control chromosomes, including 60 ethnically matched chromosomes. Family members who were heterozygous for the deletion had blue sclerae, small joint hypermobility, and corneal thickness that was more mildly reduced than that of homozygous individuals. Expression microarray analysis and quantitative PCR showed significant downregulation of genes encoding molecules involved in extracellular matrix development and maintenance, with a greater than 30-fold decrease in COL11A1 (120280), HAPLN1 (115435), and EDIL3 (606018), compared to controls. Using dermal fibroblasts from 2 affected cousins from the Pakistani family previously studied by Burkitt Wright et al. (2011), Porter et al. (2015) performed expression microarray analysis and found enrichment for genes implicated in blood vessel development and maintenance. The authors noted that 30% of upregulated and 34% of downregulated PRDM5-bound genes were ECM components, and suggested that PRDM5 directly targets ECM genes involved in blood vessel biology, consistent with the retinal capillary morphologic abnormalities seen in the patients' eyes. In addition, expression of HP1BP3 (616072) was significantly decreased in retinal tissue from the 2 patients compared to a control retina, and there was enrichment for H3K9me1/2 at upregulated ECM-related genes in patient fibroblasts, suggesting a role for H3K9-interacting proteins in PRDM5-associated disease. (less)

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

Title	Author	Journal	Year	Link
A role for repressive complexes and H3K9 di-methylation in PRDM5-associated brittle cornea syndrome.	Porter LF	Human molecular genetics	2015	PMID: 26395458
Mutations in PRDM5 in brittle cornea syndrome identify a pathway regulating extracellular matrix development and maintenance.	Burkitt Wright EMM	American journal of human genetics	2011	PMID: 21664999

Text-mined citations for this variant ...

Record last updated Sep 03, 2022

ClinVar Genomic variation as it relates to human health

NM_018699.3(PRDM5):c.946_1623del

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...