VCV001251919.1 - ClinVar

NC_000023.11:g.68119248_68212212dup

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

no assertion criteria provided

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NC_000023.11:g.68119248_68212212dup

Variation ID: 1251919 Accession: VCV001251919.1

Type and length

Duplication, 92,965 bp

Location

Cytogenetic: Xq12 X: 68119248-68212212 (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	Sep 19, 2021	Sep 19, 2021	Jul 2, 2021

HGVS

Nucleotide	Protein	Molecular consequence
NC_000023.11:g.68119248_68212212dup

Protein change

Other names

exon 7 to exon 15 duplication

Canonical SPDI

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

decreased transcript level variant; Sequence Ontology [ SO:0001541]

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.
OPHN1		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	420	563

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.
X-linked intellectual disability-cerebellar hypoplasia syndrome	Pathogenic (1)	no assertion criteria provided	Jul 2, 2021	RCV001644550.1

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 (Jul 02, 2021)	no assertion criteria provided Method: research	X-linked intellectual disability-cerebellar hypoplasia syndrome (X-linked inheritance) Affected status: yes Allele origin: germline	Institute of Science, Banaras Hindu University Additional submitter: Institute of Science, Banaras Hindu University Accession: SCV001832554.1 First in ClinVar: Sep 19, 2021 Last updated: Sep 19, 2021	Comment: Pathogenic variants in the Oligophrenin 1 gene (OPHN1) cause an X-linked intellectual disability syndrome with a phenotype typically consisting of cerebellar hypoplasia, ventriculomegaly, seizures, facial … (more) Pathogenic variants in the Oligophrenin 1 gene (OPHN1) cause an X-linked intellectual disability syndrome with a phenotype typically consisting of cerebellar hypoplasia, ventriculomegaly, seizures, facial dysmorphism, speech delay and sometimes behavioral difficulties. We describe a male patient with global developmental delay, and cerebellar hypoplasia and other neuroanatomical findings suggestive of a Dandy-Walker malformation. A clinical pontocerebellar hypoplasia sequencing plus deletion/duplication analysis panel revealed a partial duplication from exon 7 to exon 15 in OPHN1. PCR-Sanger sequencing of cDNA showed a truncating frameshift in the OPHN1 transcript. Further, transcript level analysis of OPHN1 showed a 75% reduction in the total expression in the patient in comparison to controls. Presumably this leads to a similar reduction in the level of OPHN1 protein resulting in the observed phenotype. This is the first report of a partial duplication of exons 7-15 in OPHN1 in a patient with strabismus, speech delay, dysmorphic facial features, epilepsy, an autism-like phenotype, and developmental delay. (less) Age: 0-9 years Sex: male Ethnicity/Population group: Caucasian Geographic origin: United States Comment on evidence: The clinical pontocerebellar hypoplasia sequencing plus deletion/duplication analysis panel was performed at GeneDx, Inc (Gaithersburg, MD, USA) and interrogated the following genes: CASK, CHMP1A, CLP1, … (more) The clinical pontocerebellar hypoplasia sequencing plus deletion/duplication analysis panel was performed at GeneDx, Inc (Gaithersburg, MD, USA) and interrogated the following genes: CASK, CHMP1A, CLP1, EXOSC3, OPHN1, RARS2, RELN, SEPSECS, TSEN2, TSEN34, TSEN54, TUBA1A, TUBA8, TUBB2B, TUBB3, VLDLR, VPS53, and VRK1. Targeted exons were enriched from genomic DNA by RNA probe capture using a custom Agilent SureSelect kit (Agilent Technologies, Santa Clara, CA, USA) to produce DNA libraries for next generation sequencing (NGS). The sequencing data were generated on an Illumina platform, and sequence variants were identified, filtered, and evaluated with a custom bioinformatics pipeline as previously described. (less) Method: The clinical pontocerebellar hypoplasia sequencing plus deletion/duplication analysis panel was performed at GeneDx, Inc (Gaithersburg, MD, USA) and interrogated the following genes: CASK, CHMP1A, CLP1, EXOSC3, OPHN1, RARS2, RELN, SEPSECS, TSEN2, TSEN34, TSEN54, TUBA1A, TUBA8, TUBB2B, TUBB3, VLDLR, VPS53, and VRK1. Targeted exons were enriched from genomic DNA by RNA probe capture using a custom Agilent SureSelect kit (Agilent Technologies, Santa Clara, CA, USA) to produce DNA libraries for next generation sequencing (NGS). The sequencing data were generated on an Illumina platform, and sequence variants were identified, filtered, and evaluated with a custom bioinformatics pipeline as previously described [Stosser et al., 2018]. Capillary sequencing was used to obtain sequence for regions where fewer than 15 reads were achieved by NGS. Copy number variations were also evaluated using custom exon-level array CGH (Agilent Technologies, Santa Clara, CA, USA) targeting most coding exons of the panel genes. Reporting threshold included pathogenic variants, likely pathogenic variants, and variants of uncertain significance. All reportable variants were confirmed by an orthogonal method. Testing laboratory: Gene Dx Testing laboratory interpretation: Pathogenic

Comment:

Pathogenic variants in the Oligophrenin 1 gene (OPHN1) cause an X-linked intellectual disability syndrome with a phenotype typically consisting of cerebellar hypoplasia, ventriculomegaly, seizures, facial dysmorphism, speech delay and sometimes behavioral difficulties. We describe a male patient with global developmental delay, and cerebellar hypoplasia and other neuroanatomical findings suggestive of a Dandy-Walker malformation. A clinical pontocerebellar hypoplasia sequencing plus deletion/duplication analysis panel revealed a partial duplication from exon 7 to exon 15 in OPHN1. PCR-Sanger sequencing of cDNA showed a truncating frameshift in the OPHN1 transcript. Further, transcript level analysis of OPHN1 showed a 75% reduction in the total expression in the patient in comparison to controls. Presumably this leads to a similar reduction in the level of OPHN1 protein resulting in the observed phenotype. This is the first report of a partial duplication of exons 7-15 in OPHN1 in a patient with strabismus, speech delay, dysmorphic facial features, epilepsy, an autism-like phenotype, and developmental delay.

Germline Functional Evidence

Functional Help The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence	Method Help A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter.	Result Help A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
decreased transcript level variant (SO:0001541)	The clinical pontocerebellar hypoplasia sequencing plus deletion/duplication analysis panel was performed at GeneDx, Inc (Gaithersburg, MD, USA) and interrogated the following genes: CASK, CHMP1A, CLP1, EXOSC3, OPHN1, RARS2, RELN, SEPSECS, TSEN2, TSEN34, TSEN54, TUBA1A, TUBA8, TUBB2B, TUBB3, VLDLR, VPS53, and VRK1. Targeted exons were enriched from genomic DNA by RNA probe capture using a custom Agilent SureSelect kit (Agilent Technologies, Santa Clara, CA, USA) to produce DNA libraries for next generation sequencing (NGS). The sequencing data were generated on an Illumina platform, and sequence variants were identified, filtered, and evaluated with a custom bioinformatics pipeline as previously described [Stosser et al., 2018]. Capillary sequencing was used to obtain sequence for regions where fewer than 15 reads were achieved by NGS. Copy number variations were also evaluated using custom exon-level array CGH (Agilent Technologies, Santa Clara, CA, USA) targeting most coding exons of the panel genes. Reporting threshold included pathogenic variants, likely pathogenic variants, and variants of uncertain significance. All reportable variants were confirmed by an orthogonal method.	Result not provided	Institute of Science, Banaras Hindu University Additional submitter: Institute of Science, Banaras Hindu University Accession: SCV001832554.1

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 Aug 06, 2023

ClinVar Genomic variation as it relates to human health

NC_000023.11:g.68119248_68212212dup

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...