VCV001328462.4 - ClinVar

GRCh37/hg19 12q24.31(chr12:121887337-123386068)x3

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.

Uncertain significance

criteria provided, single submitter

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

GRCh37/hg19 12q24.31(chr12:121887337-123386068)x3

Variation ID: 1328462 Accession: VCV001328462.4

Type and length

copy number gain, 1,498,732 bp

Location

Cytogenetic: 12q24.31 12: 121887337-123386068 (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	Dec 18, 2021	Dec 18, 2021	Mar 3, 2021

HGVS

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.
B3GNT4		-	-	GRCh38 GRCh37	34	91
BCL7A		-	-	GRCh38 GRCh38 GRCh37	9	38
CCDC62		-	-	GRCh38 GRCh37	52	73
CFAP251		-	-	GRCh38 GRCh37	118	147
CLIP1		-	-	GRCh38 GRCh37	129	159
DENR		-	-	GRCh38 GRCh37	13	34
DIABLO		-	-	GRCh38 GRCh37	69	153
HCAR1		-	-	GRCh38 GRCh37	34	55
HCAR2		-	-	GRCh38 GRCh37	29	53
HCAR3		-	-	GRCh38 GRCh37	24	48

There are 17 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.
not provided	Uncertain significance (1)	criteria provided, single submitter	Mar 3, 2021	RCV001795860.4

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.
Uncertain significance (Mar 03, 2021)	criteria provided, single submitter (ICSL CNVClassificationCriteria Aug2020) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Illumina Laboratory Services, Illumina Accession: SCV002037184.1 First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021	Publications: PubMed (3) PubMed: 19344873‚ 24174537‚ 25217958 Comment: This CNV is a 1.5 Mb duplication of 12q24.31, on chromosome 12, (seq[GRCh37]dup(12)(q24.31); chr12:g.21887337_123386068dup), which is inherited. This CNV constitutes a gain encompassing 27 protein … (more) This CNV is a 1.5 Mb duplication of 12q24.31, on chromosome 12, (seq[GRCh37]dup(12)(q24.31); chr12:g.21887337_123386068dup), which is inherited. This CNV constitutes a gain encompassing 27 protein coding genes. One breakpoint lies in an intergenic region and the other breakpoint is within the KDM2B gene, which does not currently have a known gene-disease relationship. Patients with similar gains in this region have not been reported in the peer-reviewed literature. There are several patients with duplications in this region in the DECIPHER database who are noted to display overlapping phenotypic features, including developmental delay (Firth et al. 2009). Several genes within this region are associated with diseases that have some overlap with the proband's reported phenotype and follow autosomal dominant inheritance, including SETD1B (MIM# 615883, intellectual developmental disorder with seizures and language delay) and ORAI1 (MIM#615883, tubular aggregate myopathy), however triplosensitivity is not currently established to cause disease for either. This CNV has not been reported in controls (MacDonald et al. 2013; Coe et al. 2014). Based on the evidence, this CNV is classified as a variant of uncertain significance. (less)

Comment:

This CNV is a 1.5 Mb duplication of 12q24.31, on chromosome 12, (seq[GRCh37]dup(12)(q24.31); chr12:g.21887337_123386068dup), which is inherited. This CNV constitutes a gain encompassing 27 protein coding genes. One breakpoint lies in an intergenic region and the other breakpoint is within the KDM2B gene, which does not currently have a known gene-disease relationship. Patients with similar gains in this region have not been reported in the peer-reviewed literature. There are several patients with duplications in this region in the DECIPHER database who are noted to display overlapping phenotypic features, including developmental delay (Firth et al. 2009). Several genes within this region are associated with diseases that have some overlap with the proband's reported phenotype and follow autosomal dominant inheritance, including SETD1B (MIM# 615883, intellectual developmental disorder with seizures and language delay) and ORAI1 (MIM#615883, tubular aggregate myopathy), however triplosensitivity is not currently established to cause disease for either. This CNV has not been reported in controls (MacDonald et al. 2013; Coe et al. 2014). Based on the evidence, this CNV is 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
Refining analyses of copy number variation identifies specific genes associated with developmental delay.	Coe BP	Nature genetics	2014	PMID: 25217958
The Database of Genomic Variants: a curated collection of structural variation in the human genome.	MacDonald JR	Nucleic acids research	2014	PMID: 24174537
DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans Using Ensembl Resources.	Firth HV	American journal of human genetics	2009	PMID: 19344873

Text-mined citations for this variant ...

Record last updated Oct 15, 2023

ClinVar Genomic variation as it relates to human health

GRCh37/hg19 12q24.31(chr12:121887337-123386068)x3

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...