VCV001808662.1 - ClinVar

GRCh37/hg19 5q33.1-35.2(chr5:150535183-172906793)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 5q33.1-35.2(chr5:150535183-172906793)x3

Variation ID: 1808662 Accession: VCV001808662.1

Type and length

copy number gain, -

Location

Cytogenetic: 5q33.1-35.2 5: 150535183-172906793 (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 16, 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.
NKX2-5		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	666	689
FBXW11		No evidence available	Little evidence for dosage pathogenicity	GRCh38 GRCh37	92	112
GABRA1		Little evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	675	712
GABRG2		Little evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	683	719
TLX3		No evidence available	No evidence available	GRCh38 GRCh37	19	36
ADAM19		-	-	GRCh38 GRCh37	89	110
ADRA1B		-	-	GRCh38 GRCh37	46	65
ANXA6		-	-	GRCh38 GRCh37	73	85
ATOX1		-	-	GRCh38 GRCh37	4	18
ATP10B		-	-	GRCh38 GRCh37	131	165

There are 90 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 16, 2022	RCV002474507.1

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 16, 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: SCV002771903.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022	Comment: The copy number gain of 5q33.1q35.2 involves numerous protein-coding genes, many of which are associated with autosomal dominant phenotypes in OMIM: SLC36A2 (OMIM 608331), FAT2 … (more) The copy number gain of 5q33.1q35.2 involves numerous protein-coding genes, many of which are associated with autosomal dominant phenotypes in OMIM: SLC36A2 (OMIM 608331), FAT2 (OMIM 604269), GLRA1 (OMIM 138491), CYFIP2 (OMIM 606323), GABRB2 (OMIM 600232), GABRA1 (OMIM 137160), GABRG2 (OMIM 137164), HMMR (OMIM 600936), KCNMB1 (OMIM 603951), FBXW11 (OMIM 605651), and NKX2-5 (OMIM 600584). Additionally, there are multiple reports of smaller copy-number-gains within the current interval; however, there is little overlap between gene content and/or phenotypes between these reports (Bestetti 2019, Dabkowska-Huc 2013, Faguer 2011, Fujita 2013, Glessner 2010, Koolen 2006, Krutzke 2016, Yu 2011). A report by Koolen et al. (2006) identified a 1.25 Mb duplication in an individual with holoprosencephaly and preaxial polydactyly. They proposed that FBXW11 is a candidate gene to explain this phenotype. Thus, based on current medical literature and gene content, this copy number variant (CNV) is interpreted as pathogenic. References: Bestetti et al., Hum Reprod. 2019 Mar 1;34(3):574-583. PMID: 30689869 Dabkowska-Huc et al., Case Rep Genet. 2013;2013:105052. PMID: 23476832 Faguer et al., Eur J Med Genet. May-Jun 2011;54(3):310-3. PMID: 21276880 Fujita et al., Am J Med Genet A. 2013 Aug;161A(8):1904-9. PMID: 23824987 Glessner et al., PLoS One. 2010 Dec 1;5(12):e15463. PMID: 21152026 Koolen et al., J Hum Genet. 2006;51(8):721-726. PMID: 16865294 Krutzke et al., Birth Defects Res A Clin Mol Teratol. 2016 Jan;106(1):16-26. PMID: 26680650 Yu et al., Rheumatology (Oxford). 2011 Jul;50(7):1201-5. PMID: 21278068 (less)

Comment:

The copy number gain of 5q33.1q35.2 involves numerous protein-coding genes, many of which are associated with autosomal dominant phenotypes in OMIM: SLC36A2 (OMIM 608331), FAT2 (OMIM 604269), GLRA1 (OMIM 138491), CYFIP2 (OMIM 606323), GABRB2 (OMIM 600232), GABRA1 (OMIM 137160), GABRG2 (OMIM 137164), HMMR (OMIM 600936), KCNMB1 (OMIM 603951), FBXW11 (OMIM 605651), and NKX2-5 (OMIM 600584). Additionally, there are multiple reports of smaller copy-number-gains within the current interval; however, there is little overlap between gene content and/or phenotypes between these reports (Bestetti 2019, Dabkowska-Huc 2013, Faguer 2011, Fujita 2013, Glessner 2010, Koolen 2006, Krutzke 2016, Yu 2011). A report by Koolen et al. (2006) identified a 1.25 Mb duplication in an individual with holoprosencephaly and preaxial polydactyly. They proposed that FBXW11 is a candidate gene to explain this phenotype. Thus, based on current medical literature and gene content, this copy number variant (CNV) is interpreted as pathogenic. References: Bestetti et al., Hum Reprod. 2019 Mar 1;34(3):574-583. PMID: 30689869 Dabkowska-Huc et al., Case Rep Genet. 2013;2013:105052. PMID: 23476832 Faguer et al., Eur J Med Genet. May-Jun 2011;54(3):310-3. PMID: 21276880 Fujita et al., Am J Med Genet A. 2013 Aug;161A(8):1904-9. PMID: 23824987 Glessner et al., PLoS One. 2010 Dec 1;5(12):e15463. PMID: 21152026 Koolen et al., J Hum Genet. 2006;51(8):721-726. PMID: 16865294 Krutzke et al., Birth Defects Res A Clin Mol Teratol. 2016 Jan;106(1):16-26. PMID: 26680650 Yu et al., Rheumatology (Oxford). 2011 Jul;50(7):1201-5. PMID: 21278068

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 5q33.1-35.2(chr5:150535183-172906793)x3

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...