VCV001808687.1 - ClinVar

GRCh37/hg19 20q11.21-11.23(chr20:29833535-34815537)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 20q11.21-11.23(chr20:29833535-34815537)x3

Variation ID: 1808687 Accession: VCV001808687.1

Type and length

copy number gain, -

Location

Cytogenetic: 20q11.21-11.23 20: 29833535-34815537 (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 1, 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.
ASXL1		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	1159	1181
GDF5		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	195	418
ACSS2		-	-	GRCh38 GRCh37	39	79
ACTL10	-	-	-	GRCh38 GRCh37	-	47
AHCY		-	-	GRCh38 GRCh37	278	316
ASIP		-	-	GRCh38 GRCh37	-	37
BCL2L1		-	-	GRCh38 GRCh37	6	36
BPIFA1		-	-	GRCh38 GRCh37	21	36
BPIFA2	-	-	-	GRCh38 GRCh37	18	34
BPIFA3	-	-	-	GRCh38 GRCh37	17	43

There are 78 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 1, 2022	RCV002474532.1

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 01, 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: SCV002771928.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022	Comment: The copy number gain of 20q11.21q11.23 involves numerous protein-coding genes, including ASXL1 (OMIM 612990) and multiple exons (NM_012156.2) of the 5' portion of EPB41L1 (OMIM … (more) The copy number gain of 20q11.21q11.23 involves numerous protein-coding genes, including ASXL1 (OMIM 612990) and multiple exons (NM_012156.2) of the 5' portion of EPB41L1 (OMIM 602879). It is not clear whether expression of EPB41L1 has been disrupted by this partial gain. One patient with autosomal dominant intellectual development disorder-11 (MRD11; OMIM 614257) has been found to have a missense variant in the EPB41L1 gene. There are 9 additional genes in this interval associated with autosomal dominant disorders in OMIM, including: ASXL1, MYLK2 (OMIM 606566), POFUT1 (OMIM 607491), KIF3B (OMIM 603754), DNMT3B (OMIM 602900), SNTA1 (OMIM 601017), CHMP4B (OMIM 610897), GDF5 (OMIM 601146), and RBM12 (OMIM 607179). Furthermore, copy number gains that partially overlap the current interval have been associated with 20q11.2 microduplication syndrome, which is characterized by metopic ridging/trigonocephaly, developmental delay, epicanthal folds, and short hands (Avila 2013). It is hypothesized that the involvement of the ASXL1 gene explains at least a part of this phenotype; however, the reported gains associated with this microduplication syndrome contain additional genetic material in comparison to the current interval (D'Angelo 2018, Goetzinger 2021, Gurkan 2020). Otherwise, copy number gains of this particular interval have not yet been associated with a specific clinical phenotype, yet 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 likely pathogenic. References: Avila et al., Am J Med Genet A. 2013 Jul;161A(7):1594-8. PMID: 23704076. D'Angelo et al., Mol Cytogenet. 2018 Feb 5;11:14. PMID: 29441128. Goetzinger et al., Mol Genet Genomic Med. 2021 Aug;9(8):e1755. PMID: 34268909. Gurkan et al., Noro Psikiyatr Ars. 2020 May 5;57(3):177-191. PMID: 32952419. (less)

Comment:

The copy number gain of 20q11.21q11.23 involves numerous protein-coding genes, including ASXL1 (OMIM 612990) and multiple exons (NM_012156.2) of the 5' portion of EPB41L1 (OMIM 602879). It is not clear whether expression of EPB41L1 has been disrupted by this partial gain. One patient with autosomal dominant intellectual development disorder-11 (MRD11; OMIM 614257) has been found to have a missense variant in the EPB41L1 gene. There are 9 additional genes in this interval associated with autosomal dominant disorders in OMIM, including: ASXL1, MYLK2 (OMIM 606566), POFUT1 (OMIM 607491), KIF3B (OMIM 603754), DNMT3B (OMIM 602900), SNTA1 (OMIM 601017), CHMP4B (OMIM 610897), GDF5 (OMIM 601146), and RBM12 (OMIM 607179). Furthermore, copy number gains that partially overlap the current interval have been associated with 20q11.2 microduplication syndrome, which is characterized by metopic ridging/trigonocephaly, developmental delay, epicanthal folds, and short hands (Avila 2013). It is hypothesized that the involvement of the ASXL1 gene explains at least a part of this phenotype; however, the reported gains associated with this microduplication syndrome contain additional genetic material in comparison to the current interval (D'Angelo 2018, Goetzinger 2021, Gurkan 2020). Otherwise, copy number gains of this particular interval have not yet been associated with a specific clinical phenotype, yet 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 likely pathogenic. References: Avila et al., Am J Med Genet A. 2013 Jul;161A(7):1594-8. PMID: 23704076. D'Angelo et al., Mol Cytogenet. 2018 Feb 5;11:14. PMID: 29441128. Goetzinger et al., Mol Genet Genomic Med. 2021 Aug;9(8):e1755. PMID: 34268909. Gurkan et al., Noro Psikiyatr Ars. 2020 May 5;57(3):177-191. PMID: 32952419.

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 20q11.21-11.23(chr20:29833535-34815537)x3

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...