VCV001808681.1 - ClinVar

GRCh37/hg19 8q21.12-24.11(chr8:79409349-119040631)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.

Pathogenic

criteria provided, single submitter

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

GRCh37/hg19 8q21.12-24.11(chr8:79409349-119040631)x3

Variation ID: 1808681 Accession: VCV001808681.1

Type and length

copy number gain, -

Location

Cytogenetic: 8q21.12-24.11 8: 79409349-119040631 (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 31, 2022	Dec 31, 2022	May 31, 2022

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.
EXT1		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	999	1074
NBN		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	3422	3595
RAD21		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	384	448
TRPS1		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	622	685
ZFPM2		Little evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	72	377
IMPA1		No evidence available	No evidence available	GRCh38 GRCh37	30	73
AARD	-	-	-	GRCh38 GRCh37	5	67
ABRA		-	-	GRCh38 GRCh37	44	84
ANGPT1		-	-	GRCh38 GRCh37	240	287
ANKRD46	-	-	-	GRCh38 GRCh37	12	53

There are 133 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)	criteria provided, single submitter	May 31, 2022	RCV002474526.1

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 (May 31, 2022)	criteria provided, single submitter (ACMG/ClinGen CNV Guidelines, 2019) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Quest Diagnostics Nichols Institute San Juan Capistrano Accession: SCV002771922.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022	Comment: The copy number gain of 8q21.12q24.11 involves numerous protein-coding genes, including GDF6 (OMIM 601147), SDC2 (OMIM 142460), and multiple exons (NM_000127.3) of the 3' portion … (more) The copy number gain of 8q21.12q24.11 involves numerous protein-coding genes, including GDF6 (OMIM 601147), SDC2 (OMIM 142460), and multiple exons (NM_000127.3) of the 3' portion of EXT1 (OMIM 608177). It is not clear whether expression of EXT1 has been disrupted by this partial gain. Haploinsufficiency of EXT1 is associated with autosomal dominant multiple osteochondromas (MO), a heterogeneous disease with variable number and size of osteochondromas, as well as changeable number and location of diseased bones (Guo 2017, Li 2018, Santos 2018). Additionally, microduplications at 8q22.1 encompassing GDF6 and SDC2 have been reported in two individuals with Leri's pleonosteosis (LP; OMIM 151200), which is an autosomal dominant rheumatic condition characterized by flexion contractures of the interphalangeal joints, limited motion of multiple joints, and short broad metacarpals, metatarsals and phalanges (Banka 2015). Duplications similar to or smaller than the current interval have also been identified in individuals with phenotypes including epilepsy, developmental delay, and dysmorphic facial features (Leary 2019, Rezazadeh 2017). Finally, there are twelve genes in this copy number loss that are associated with autosomal dominant disorders. There are no similar copy number gains of this region in the general populations of the Database of Genomic Variants. Thus, based on current medical literature and gene content, this copy number variant (CNV) is interpreted as pathogenic. References: Banka et al. Ann Rheum Dis. 2015 Jun;74(6):1249-56. PMID: 24442880. Guo et al. Tohoku J Exp Med. 2017 Jul;242(3):173-181. PMID: 28690282. Leary et al. Clin Case Rep. 2019 Oct 24;7(12):2393-2397. PMID: 31893066. Rezazadeh et al. Seizure. 2017 May;48:57-61. PMID: 28419948. Santos et al. Mol Genet Genomic Med. 2018 May;6(3):382-392. PMID: 29529714. (less)

Comment:

The copy number gain of 8q21.12q24.11 involves numerous protein-coding genes, including GDF6 (OMIM 601147), SDC2 (OMIM 142460), and multiple exons (NM_000127.3) of the 3' portion of EXT1 (OMIM 608177). It is not clear whether expression of EXT1 has been disrupted by this partial gain. Haploinsufficiency of EXT1 is associated with autosomal dominant multiple osteochondromas (MO), a heterogeneous disease with variable number and size of osteochondromas, as well as changeable number and location of diseased bones (Guo 2017, Li 2018, Santos 2018). Additionally, microduplications at 8q22.1 encompassing GDF6 and SDC2 have been reported in two individuals with Leri's pleonosteosis (LP; OMIM 151200), which is an autosomal dominant rheumatic condition characterized by flexion contractures of the interphalangeal joints, limited motion of multiple joints, and short broad metacarpals, metatarsals and phalanges (Banka 2015). Duplications similar to or smaller than the current interval have also been identified in individuals with phenotypes including epilepsy, developmental delay, and dysmorphic facial features (Leary 2019, Rezazadeh 2017). Finally, there are twelve genes in this copy number loss that are associated with autosomal dominant disorders. There are no similar copy number gains of this region in the general populations of the Database of Genomic Variants. Thus, based on current medical literature and gene content, this copy number variant (CNV) is interpreted as pathogenic. References: Banka et al. Ann Rheum Dis. 2015 Jun;74(6):1249-56. PMID: 24442880. Guo et al. Tohoku J Exp Med. 2017 Jul;242(3):173-181. PMID: 28690282. Leary et al. Clin Case Rep. 2019 Oct 24;7(12):2393-2397. PMID: 31893066. Rezazadeh et al. Seizure. 2017 May;48:57-61. PMID: 28419948. Santos et al. Mol Genet Genomic Med. 2018 May;6(3):382-392. PMID: 29529714.

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 Dec 31, 2022

ClinVar Genomic variation as it relates to human health

GRCh37/hg19 8q21.12-24.11(chr8:79409349-119040631)x3

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...