VCV003061841.1 - ClinVar

GRCh38/hg38 10q26.2-26.3(chr10:125976998-133427130)x1

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

GRCh38/hg38 10q26.2-26.3(chr10:125976998-133427130)x1

Variation ID: 3061841 Accession: VCV003061841.1

Type and length

copy number loss, 7,450,133 bp

Location

Cytogenetic: 10q26.2-26.3 10: 125976998-133427130 (GRCh38) [ 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 17, 2024	Mar 16, 2024	Mar 12, 2024

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.
EBF3		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	244	345
ADAM12		-	-	GRCh38 GRCh37	62	135
ADAM8		-	-	GRCh38 GRCh37	101	214
ADGRA1		-	-	GRCh38 GRCh37	52	166
ADGRA1-AS1	-	-	-	GRCh38	-	43
AS-PTPRE	-	-	-	GRCh38	-	32
BNIP3		-	-	GRCh38 GRCh37	5	116
C10orf143	-	-	-	GRCh38	-	36
C10orf90		-	-	GRCh38 GRCh37	14	87
CALY		-	-	GRCh38 GRCh37	-	127

There are 193 more genes affected by this variant. See the full set of genes in Variation Viewer (GRCh38).

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.
Duane syndrome type 1 Hypotonia, ataxia, and delayed development syndrome	Pathogenic (1)	criteria provided, single submitter	Mar 12, 2024	RCV003984306.3

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 (Mar 12, 2024)	criteria provided, single submitter (ACMG/ClinGen CNV Guidelines, 2019) Method: research	Duane syndrome type 1 Hypotonia, ataxia, and delayed development syndrome Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. (Autosomal dominant inheritance) Affected status: yes Allele origin: de novo	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard Accession: SCV004800996.1 First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024	Publications: PubMed (4) PubMed: 39033378‚ 31690835‚ 29162653‚ 35340043 Comment: A confirmed de novo heterozygous 10q deletion of 32 genes (https://genescout.omim.org/) was identified by genome sequencing in two unrelated individuals with multisystem phenotypes including Duane … (more) A confirmed de novo heterozygous 10q deletion of 32 genes (https://genescout.omim.org/) was identified by genome sequencing in two unrelated individuals with multisystem phenotypes including Duane retraction syndrome, scoliosis, autism, developmental delays, and hypotonia via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Engle lab (https://kirbyneuro.org/EngleLab/) ([GRCh 38] chr10:125976998_133427130x1). There is complete overlap with the EBF3 gene, which is suspected to be haploinsufficient but has not been assessed by the ClinGen Dosage Sensitivity Working Group. Though dosage sensitivity has not been established, DECIPHER has predicted the EBF3 gene to be haploinsufficient. At least six reported probands from the literature (PMID: 29162653, 35340043) have loss of function variants in EBF3. The variants reported are de novo and the reported phenotypes (hypotonia, ataxia, autism, intellectual disability, and delayed development) are nonspecific. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant chromosome 10q deletion syndrome. The ACMG/ClinGen evidence codes and points used in this curation are as follows: 1: 0 points, 2: 0.15 points, 3: 0.45 points, 4-5: 0.70 points Total: 1.30 points; Riggs 2020 (PMID: 31690835). (less)

Comment:

A confirmed de novo heterozygous 10q deletion of 32 genes (https://genescout.omim.org/) was identified by genome sequencing in two unrelated individuals with multisystem phenotypes including Duane retraction syndrome, scoliosis, autism, developmental delays, and hypotonia via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Engle lab (https://kirbyneuro.org/EngleLab/) ([GRCh 38] chr10:125976998_133427130x1). There is complete overlap with the EBF3 gene, which is suspected to be haploinsufficient but has not been assessed by the ClinGen Dosage Sensitivity Working Group. Though dosage sensitivity has not been established, DECIPHER has predicted the EBF3 gene to be haploinsufficient. At least six reported probands from the literature (PMID: 29162653, 35340043) have loss of function variants in EBF3. The variants reported are de novo and the reported phenotypes (hypotonia, ataxia, autism, intellectual disability, and delayed development) are nonspecific. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant chromosome 10q deletion syndrome. The ACMG/ClinGen evidence codes and points used in this curation are as follows: 1: 0 points, 2: 0.15 points, 3: 0.45 points, 4-5: 0.70 points Total: 1.30 points; Riggs 2020 (PMID: 31690835).

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
Expanding the genetics and phenotypes of ocular congenital cranial dysinnervation disorders.	Jurgens JA	Genetics in medicine : official journal of the American College of Medical Genetics	2024	PMID: 39033378
An Integrated Phenotypic and Genotypic Approach Reveals a High-Risk Subtype Association for EBF3 Missense Variants Affecting the Zinc Finger Domain.	Deisseroth CA	Annals of neurology	2022	PMID: 35340043
Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen).	Riggs ER	Genetics in medicine : official journal of the American College of Medical Genetics	2020	PMID: 31690835
De novo variants in EBF3 are associated with hypotonia, developmental delay, intellectual disability, and autism.	Tanaka AJ	Cold Spring Harbor molecular case studies	2017	PMID: 29162653

Text-mined citations for this variant ...

Record last updated Aug 18, 2024

ClinVar Genomic variation as it relates to human health

GRCh38/hg38 10q26.2-26.3(chr10:125976998-133427130)x1

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...