VCV001409651.38 - ClinVar

NC_000021.8:g.(?_32439271)_(39212984_?)dup

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.

(4)

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

NC_000021.8:g.(?_32439271)_(39212984_?)dup

Variation ID: 1409651 Accession: VCV001409651.38

Type and length

Duplication, 6,773,714 bp

Location

Cytogenetic: 21q22.11-22.13 21: 32439271-39212984 (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	Jun 29, 2024	Jan 23, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NC_000021.8:g.(?_32439271)_(39212984_?)dup

Protein change

Other names

Canonical SPDI

Functional
consequence

The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele
frequency (GMAF)

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

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.
DYRK1A		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	970	1046
RUNX1		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	1252	1606
SON		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	1289	1373
ITSN1		Little evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	234	304
DNAJC28	-	Dosage sensitivity unlikely	No evidence available	GRCh38 GRCh38 GRCh37	22	88
RCAN1		No evidence available	No evidence available	GRCh38 GRCh37	11	88
VPS26C		No evidence available	No evidence available	GRCh38 GRCh37	25	96
ATP5PO		-	-	GRCh38 GRCh37	10	81
CBR1		-	-	GRCh38 GRCh37	-	91
CBR3		-	-	GRCh38 GRCh37	1	93

There are 40 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.
Amyotrophic lateral sclerosis type 1	Uncertain significance (1)	criteria provided, single submitter	Oct 7, 2022	RCV001939883.11
DYRK1A-related intellectual disability syndrome	Uncertain significance (1)	criteria provided, single submitter	Oct 27, 2022	RCV003107882.10
Immunodeficiency 28	Uncertain significance (1)	criteria provided, single submitter	Jan 23, 2024	RCV004579581.1
Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1	Uncertain significance (1)	criteria provided, single submitter	Jan 23, 2024	RCV004579580.1

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.
Uncertain significance (Oct 07, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Amyotrophic lateral sclerosis type 1 Affected status: unknown Allele origin: germline	Invitae Accession: SCV002186768.3 First in ClinVar: Mar 28, 2022 Last updated: Nov 11, 2023	Comment: A copy number gain of the genomic region encompassing the full coding sequence of the SOD1 gene has been identified. The boundaries of this event … (more) A copy number gain of the genomic region encompassing the full coding sequence of the SOD1 gene has been identified. The boundaries of this event are unknown as they extend beyond the assayed region for this gene and therefore may encompass additional genes. As the precise location of this event is unknown, it may be in tandem or it may be located elsewhere in the genome. A similar copy number variant has been observed in individual(s) with clinical features of amyotrophic lateral sclerosis (Invitae). 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)
Uncertain significance (Oct 27, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	DYRK1A-related intellectual disability syndrome Affected status: unknown Allele origin: germline	Invitae Accession: SCV003793571.2 First in ClinVar: Feb 13, 2023 Last updated: Nov 11, 2023	Publications: PubMed (2) PubMed: 17237124‚ 23512985 Comment: A copy number gain of the genomic region encompassing the full coding sequence of the DYRK1A gene has been identified. The boundaries of this event … (more) A copy number gain of the genomic region encompassing the full coding sequence of the DYRK1A gene has been identified. The boundaries of this event are unknown as they extend beyond the assayed region for this gene and therefore may encompass additional genes. As the precise location of this event is unknown, it may be in tandem or it may be located elsewhere in the genome. Isolated whole-gene copy number gains of DYRK1A have not been reported in the literature. However, larger copy number events that include this gene have been reported (PMID: 17237124, 23512985). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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)
Uncertain significance (Jan 23, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1 Affected status: unknown Allele origin: unknown	Invitae Accession: SCV005068070.1 First in ClinVar: Jun 29, 2024 Last updated: Jun 29, 2024	Comment: A copy number gain of the genomic region encompassing the full coding sequence of the RUNX1 gene has been identified. The boundaries of this event … (more) A copy number gain of the genomic region encompassing the full coding sequence of the RUNX1 gene has been identified. The boundaries of this event are unknown as they extend beyond the assayed region for this gene and therefore may encompass additional genes. As the precise location of this event is unknown, it may be in tandem or it may be located elsewhere in the genome. A similar copy number variant has been observed in individual(s) with pancytopenia (Invitae). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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)
Uncertain significance (Jan 23, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Immunodeficiency 28 Affected status: unknown Allele origin: unknown	Invitae Accession: SCV005068082.1 First in ClinVar: Jun 29, 2024 Last updated: Jun 29, 2024	Comment: A copy number gain of the genomic region encompassing the full coding sequence of the IFNGR2 gene has been identified. The boundaries of this event … (more) A copy number gain of the genomic region encompassing the full coding sequence of the IFNGR2 gene has been identified. The boundaries of this event are unknown as they extend beyond the assayed region for this gene and therefore may encompass additional genes. As the precise location of this event is unknown, it may be in tandem or it may be located elsewhere in the genome. This variant has not been reported in the literature in individuals affected with IFNGR2-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)

Comment:

A copy number gain of the genomic region encompassing the full coding sequence of the SOD1 gene has been identified. The boundaries of this event are unknown as they extend beyond the assayed region for this gene and therefore may encompass additional genes. As the precise location of this event is unknown, it may be in tandem or it may be located elsewhere in the genome. A similar copy number variant has been observed in individual(s) with clinical features of amyotrophic lateral sclerosis (Invitae). 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.

Comment:

A copy number gain of the genomic region encompassing the full coding sequence of the DYRK1A gene has been identified. The boundaries of this event are unknown as they extend beyond the assayed region for this gene and therefore may encompass additional genes. As the precise location of this event is unknown, it may be in tandem or it may be located elsewhere in the genome. Isolated whole-gene copy number gains of DYRK1A have not been reported in the literature. However, larger copy number events that include this gene have been reported (PMID: 17237124, 23512985). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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.

Comment:

A copy number gain of the genomic region encompassing the full coding sequence of the RUNX1 gene has been identified. The boundaries of this event are unknown as they extend beyond the assayed region for this gene and therefore may encompass additional genes. As the precise location of this event is unknown, it may be in tandem or it may be located elsewhere in the genome. A similar copy number variant has been observed in individual(s) with pancytopenia (Invitae). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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.

Comment:

A copy number gain of the genomic region encompassing the full coding sequence of the IFNGR2 gene has been identified. The boundaries of this event are unknown as they extend beyond the assayed region for this gene and therefore may encompass additional genes. As the precise location of this event is unknown, it may be in tandem or it may be located elsewhere in the genome. This variant has not been reported in the literature in individuals affected with IFNGR2-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
Triplication of DYRK1A causes retinal structural and functional alterations in Down syndrome.	Laguna A	Human molecular genetics	2013	PMID: 23512985
Familial 4.3 Mb duplication of 21q22 sheds new light on the Down syndrome critical region.	Ronan A	Journal of medical genetics	2007	PMID: 17237124

Text-mined citations for this variant ...

Record last updated Sep 17, 2024

ClinVar Genomic variation as it relates to human health

NC_000021.8:g.(?_32439271)_(39212984_?)dup

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...