VCV002425922.27 - ClinVar

NC_000005.9:g.(?_175158654)_(179263593_?)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.

(3)

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_000005.9:g.(?_175158654)_(179263593_?)dup

Variation ID: 2425922 Accession: VCV002425922.27

Type and length

Duplication, 4,104,940 bp

Location

Cytogenetic: 5q35.2-35.3 5: 175158654-179263593 (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, 2023	Nov 11, 2023	Aug 3, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NC_000005.9:g.(?_175158654)_(179263593_?)dup

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.
DDX41		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	581	649
NSD1		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	1749	1865
ADAMTS2		-	-	GRCh38 GRCh38 GRCh37	1769	1824
ARL10	-	-	-	GRCh38 GRCh37	12	91
B4GALT7		-	-	GRCh38 GRCh37	327	418
CANX		-	-	GRCh38 GRCh38 GRCh37	29	89
CBY3		-	-	GRCh38 GRCh38 GRCh37	1	61
CDHR2		-	-	GRCh38 GRCh37	110	168
CLK4		-	-	GRCh38 GRCh37	21	60
CLTB		-	-	GRCh38 GRCh37	-	57

There are 55 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.
Ehlers-Danlos syndrome, dermatosparaxis type	no classifications from unflagged records (1)	no classifications from unflagged records	-	RCV003116717.13
Sotos syndrome	no classifications from unflagged records (1)	no classifications from unflagged records	-	RCV003232857.11
not provided	Uncertain significance (1)	criteria provided, single submitter	Aug 3, 2022	RCV003154288.9

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 (Aug 03, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003843969.1 First in ClinVar: Mar 26, 2023 Last updated: Mar 26, 2023	Comment: A copy number gain of the genomic region encompassing the full coding sequence of the DDX41 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 DDX41 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 DDX41-related conditions. 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 (Jul 25, 2022)	Flagged submission flagged submission (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing Reason: This record appears to be redundant with a more recent record from the same submitter. Notes: SCV003792926 appears to (...more) Source: NCBI	Ehlers-Danlos syndrome, dermatosparaxis type Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003792926.2 First in ClinVar: Feb 13, 2023 Last updated: Nov 11, 2023	Comment: A copy number gain of the genomic region encompassing the full coding sequence of the ADAMTS2 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 ADAMTS2 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 ADAMTS2-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)
Uncertain significance (Jul 25, 2022)	Flagged submission flagged submission (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing Reason: This record appears to be redundant with a more recent record from the same submitter. Notes: SCV003791914 appears to (...more) Source: NCBI	None Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003791914.2 First in ClinVar: Feb 13, 2023 Last updated: Jun 10, 2023	Publications: PubMed (8) PubMed: 16770806‚ 17090394‚ 21567906‚ 23599694‚ 23913520‚ 24819041‚ 28128410‚ 33389145 Comment: A copy number gain of the genomic region encompassing the full coding sequence of the NSD1 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 NSD1 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 NSD1 have not been reported in the literature. However, larger copy number events that include this gene have been reported (PMID: 16770806, 17090394, 21567906, 23599694, 23913520, 24819041, 28128410, 33389145). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that a similar copy number variant affects NSD1 function (PMID: 33389145). 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)
Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more

Comment:

A copy number gain of the genomic region encompassing the full coding sequence of the DDX41 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 DDX41-related conditions. 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 ADAMTS2 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 ADAMTS2-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.

Comment:

A copy number gain of the genomic region encompassing the full coding sequence of the NSD1 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 NSD1 have not been reported in the literature. However, larger copy number events that include this gene have been reported (PMID: 16770806, 17090394, 21567906, 23599694, 23913520, 24819041, 28128410, 33389145). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that a similar copy number variant affects NSD1 function (PMID: 33389145). 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
5q35 duplication presents with psychiatric and undergrowth phenotypes mediated by NSD1 overexpression and mTOR signaling downregulation.	Quintero-Rivera F	Human genetics	2021	PMID: 33389145
A rare case of a boy with de novo microduplication at 5q35.2q35.3 from central Brazil.	Reis FG	Genetics and molecular research : GMR	2017	PMID: 28128410
Defining the phenotype associated with microduplication reciprocal to Sotos syndrome microdeletion.	Novara F	American journal of medical genetics. Part A	2014	PMID: 24819041
The phenotypic spectrum of duplication 5q35.2-q35.3 encompassing NSD1: is it really a reversed Sotos syndrome?	Dikow N	American journal of medical genetics. Part A	2013	PMID: 23913520
Further Evidence of Contrasting Phenotypes Caused by Reciprocal Deletions and Duplications: Duplication of NSD1 Causes Growth Retardation and Microcephaly.	Rosenfeld JA	Molecular syndromology	2013	PMID: 23599694
Reversed clinical phenotype due to a microduplication of Sotos syndrome region detected by array CGH: microcephaly, developmental delay and delayed bone age.	Zhang H	American journal of medical genetics. Part A	2011	PMID: 21567906
MLPA analysis for a panel of syndromes with mental retardation reveals imbalances in 5.8% of patients with mental retardation and dysmorphic features, including duplications of the Sotos syndrome and Williams-Beuren syndrome regions.	Kirchhoff M	European journal of medical genetics	2007	PMID: 17090394
Molecular cytogenetic analysis of de novo dup(5)(q35.2q35.3) and review of the literature of pure partial trisomy 5q.	Chen CP	American journal of medical genetics. Part A	2006	PMID: 16770806

Text-mined citations for this variant ...

Record last updated Nov 19, 2024

ClinVar Genomic variation as it relates to human health

NC_000005.9:g.(?_175158654)_(179263593_?)dup

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...