VCV001808750.1 - ClinVar

GRCh37/hg19 5q35.2-35.3(chr5:176516440-177773252)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.

Likely pathogenic

criteria provided, single submitter

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

GRCh37/hg19 5q35.2-35.3(chr5:176516440-177773252)x3

Variation ID: 1808750 Accession: VCV001808750.1

Type and length

copy number gain, -

Location

Cytogenetic: 5q35.2-35.3 5: 176516440-177773252 (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	Jun 8, 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.
DDX41		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	581	649
NSD1		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	1747	1863
B4GALT7		-	-	GRCh38 GRCh37	327	418
COL23A1		-	-	GRCh38 GRCh37	37	80
DBN1		-	-	GRCh38 GRCh37	50	114
DOK3		-	-	GRCh38 GRCh37	52	126
F12		-	-	GRCh38 GRCh37	158	239
FAM153A	-	-	-	GRCh38 GRCh37	19	74
FAM193B		-	-	GRCh38 GRCh37	62	127
FGFR4		-	-	GRCh38 GRCh37	70	132

There are 17 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	Likely pathogenic (1)	criteria provided, single submitter	Jun 8, 2021	RCV002474595.1

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.
Likely pathogenic (Jun 08, 2021)	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: SCV002771991.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022	Comment: The copy number gain of 5q35.2q35.3 involves multiple protein-coding genes, including NSD1 (OMIM 606681), SLC34A1 (OMIM 182309), and F12 (OMIM 610619). Haploinsufficiency of NSD1 is … (more) The copy number gain of 5q35.2q35.3 involves multiple protein-coding genes, including NSD1 (OMIM 606681), SLC34A1 (OMIM 182309), and F12 (OMIM 610619). Haploinsufficiency of NSD1 is associated with Sotos syndrome 1 (OMIM 117550). The NSD1 gene however is not currently classified as triplosensitive although it is contained within the shortest region of overlap within a larger 5q35 recurrent region associated with \reversed\" Sotos syndrome phenotype, commonly including short stature, microcephaly, delayed bone age, and developmental delay/intellectual disability. Case reports with smaller overlapping duplications of this region, and include NSD1, were described with Silver-Russell syndrome (SRS) and three with reverse Sotos syndrome (Kirchhoff et al., Eur J Med Genet. Jan-Feb2007;50(1):33-42. PMID: 17090394; Reis et al., Genet Mol Res. 2017Jan 23;16(1). PMID: 28128410; Sachwitz et al., Clin Genet. 2017Jan;91(1):73-78. PMID: 27172843; Rosenfeld et al., Mol Syndromol.2013 Jan;3(6):247-54. PMID: 23599694). The individual with SRS carried a de novo 381 Kb duplication. Two individuals with reverse Sotos syndrome carried de novo duplications and one carried a maternally inherited duplication. All patients had phenotypes involving growth retardation and facial anomalies. Heterozygous sequence variants of SLC34A1 and F12 are associated with autosomal dominant disorders, hypophosphatemic nephrolithiasis/osteoporosis-1 (OMIM 612286) and hereditary angioedema type III (OMIM 610618), respectively. There are no similar copy number gains of this region in the general populations of the Database of Genomic Variants. Thus, the clinical significance of this copy number variant (CNV) is likely pathogenic." (less)

Comment:

The copy number gain of 5q35.2q35.3 involves multiple protein-coding genes, including NSD1 (OMIM 606681), SLC34A1 (OMIM 182309), and F12 (OMIM 610619). Haploinsufficiency of NSD1 is associated with Sotos syndrome 1 (OMIM 117550). The NSD1 gene however is not currently classified as triplosensitive although it is contained within the shortest region of overlap within a larger 5q35 recurrent region associated with \reversed\" Sotos syndrome phenotype, commonly including short stature, microcephaly, delayed bone age, and developmental delay/intellectual disability. Case reports with smaller overlapping duplications of this region, and include NSD1, were described with Silver-Russell syndrome (SRS) and three with reverse Sotos syndrome (Kirchhoff et al., Eur J Med Genet. Jan-Feb2007;50(1):33-42. PMID: 17090394; Reis et al., Genet Mol Res. 2017Jan 23;16(1). PMID: 28128410; Sachwitz et al., Clin Genet. 2017Jan;91(1):73-78. PMID: 27172843; Rosenfeld et al., Mol Syndromol.2013 Jan;3(6):247-54. PMID: 23599694). The individual with SRS carried a de novo 381 Kb duplication. Two individuals with reverse Sotos syndrome carried de novo duplications and one carried a maternally inherited duplication. All patients had phenotypes involving growth retardation and facial anomalies. Heterozygous sequence variants of SLC34A1 and F12 are associated with autosomal dominant disorders, hypophosphatemic nephrolithiasis/osteoporosis-1 (OMIM 612286) and hereditary angioedema type III (OMIM 610618), respectively. There are no similar copy number gains of this region in the general populations of the Database of Genomic Variants. Thus, the clinical significance of this copy number variant (CNV) is likely pathogenic."

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 Mar 26, 2023

ClinVar Genomic variation as it relates to human health

GRCh37/hg19 5q35.2-35.3(chr5:176516440-177773252)x3

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...