VCV001456057.10 - ClinVar

NC_000002.11:g.(?_201943606)_(204824322_?)del

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.

(3)

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

NC_000002.11:g.(?_201943606)_(204824322_?)del

Variation ID: 1456057 Accession: VCV001456057.10

Type and length

Deletion, 2,880,717 bp

Location

Cytogenetic: 2q33.1-33.2 2: 201943606-204824322 (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	Mar 28, 2022	Nov 11, 2023	Jun 20, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NC_000002.11:g.(?_201943606)_(204824322_?)del

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.
BMPR2		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	1091	1154
CASP10		Little evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	520	554
ABI2		-	-	GRCh38 GRCh37	13	43
ALS2		-	-	GRCh38 GRCh37	1009	1053
C2CD6		-	-	GRCh38 GRCh37	102	140
CARF		-	-	GRCh38 GRCh37	47	79
CASP8		-	-	GRCh38 GRCh37	321	363
CD28		-	-	GRCh38 GRCh37	10	45
CDK15		-	-	GRCh38 GRCh37	23	58
CFLAR		-	-	GRCh38 GRCh37	12	52

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.
Autoimmune lymphoproliferative syndrome type 2B	Pathogenic (1)	criteria provided, single submitter	Jun 20, 2022	RCV001950955.5
Autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency	Pathogenic (1)	criteria provided, single submitter	Jun 20, 2022	RCV001950956.7
Immunodeficiency, common variable, 1	Pathogenic (1)	criteria provided, single submitter	Jun 20, 2022	RCV003120780.4

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 (Jun 20, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002231755.3 First in ClinVar: Mar 28, 2022 Last updated: Nov 11, 2023	Publications: PubMed (4) PubMed: 25213377‚ 25329329‚ 29729943‚ 30326257 Comment: A gross deletion of the genomic region encompassing the full coding sequence of the CTLA4 gene has been identified. Loss-of-function variants in CTLA4 are known … (more) A gross deletion of the genomic region encompassing the full coding sequence of the CTLA4 gene has been identified. Loss-of-function variants in CTLA4 are known to be pathogenic (PMID: 25213377, 25329329). The boundaries of this event are unknown as they extend beyond the assayed region for this gene and therefore may encompass additional genes. Isolated whole-gene deletions of CTLA4 have not been reported in the literature. However, larger copy number events that include this gene have been reported (PMID: 29729943, 30326257). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Jun 20, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Autoimmune lymphoproliferative syndrome type 2B Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002242045.3 First in ClinVar: Mar 28, 2022 Last updated: Nov 11, 2023	Publications: PubMed (2) PubMed: 12353035‚ 25814141 Comment: A gross deletion of the genomic region encompassing the full coding sequence of the CASP8 gene has been identified. Loss-of-function variants in CASP8 are known … (more) A gross deletion of the genomic region encompassing the full coding sequence of the CASP8 gene has been identified. Loss-of-function variants in CASP8 are known to be pathogenic (PMID: 12353035, 25814141). The boundaries of this event are unknown as they extend beyond the assayed region for this gene and therefore may encompass additional genes. This variant has not been reported in the literature in individuals affected with CASP8-related conditions. For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Jun 20, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Immunodeficiency, common variable, 1 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003792756.2 First in ClinVar: Feb 13, 2023 Last updated: Nov 11, 2023	Publications: PubMed (3) PubMed: 11343122‚ 12577056‚ 19380800 Comment: A gross deletion of the genomic region encompassing the full coding sequence of the ICOS gene has been identified. Loss-of-function variants in ICOS are known … (more) A gross deletion of the genomic region encompassing the full coding sequence of the ICOS gene has been identified. Loss-of-function variants in ICOS are known to be pathogenic (PMID: 11343122, 12577056, 19380800). The boundaries of this event are unknown as they extend beyond the assayed region for this gene and therefore may encompass additional genes. This variant has not been reported in the literature in individuals affected with ICOS-related conditions. For these reasons, this variant has been classified as Pathogenic. (less)

Comment:

A gross deletion of the genomic region encompassing the full coding sequence of the CTLA4 gene has been identified. Loss-of-function variants in CTLA4 are known to be pathogenic (PMID: 25213377, 25329329). The boundaries of this event are unknown as they extend beyond the assayed region for this gene and therefore may encompass additional genes. Isolated whole-gene deletions of CTLA4 have not been reported in the literature. However, larger copy number events that include this gene have been reported (PMID: 29729943, 30326257). For these reasons, this variant has been classified as Pathogenic.

Comment:

A gross deletion of the genomic region encompassing the full coding sequence of the CASP8 gene has been identified. Loss-of-function variants in CASP8 are known to be pathogenic (PMID: 12353035, 25814141). The boundaries of this event are unknown as they extend beyond the assayed region for this gene and therefore may encompass additional genes. This variant has not been reported in the literature in individuals affected with CASP8-related conditions. For these reasons, this variant has been classified as Pathogenic.

Comment:

A gross deletion of the genomic region encompassing the full coding sequence of the ICOS gene has been identified. Loss-of-function variants in ICOS are known to be pathogenic (PMID: 11343122, 12577056, 19380800). The boundaries of this event are unknown as they extend beyond the assayed region for this gene and therefore may encompass additional genes. This variant has not been reported in the literature in individuals affected with ICOS-related conditions. For these reasons, this variant has been classified as 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

Title	Author	Journal	Year	Link
A de novo monoallelic CTLA-4 deletion causing pediatric onset CVID with recurrent autoimmune cytopenias and severe enteropathy.	Lougaris V	Clinical immunology (Orlando, Fla.)	2018	PMID: 30326257
Phenotype, penetrance, and treatment of 133 cytotoxic T-lymphocyte antigen 4-insufficient subjects.	Schwab C	The Journal of allergy and clinical immunology	2018	PMID: 29729943
Caspase-8 Deficiency Presenting as Late-Onset Multi-Organ Lymphocytic Infiltration with Granulomas in two Adult Siblings.	Niemela J	Journal of clinical immunology	2015	PMID: 25814141
Autosomal dominant immune dysregulation syndrome in humans with CTLA4 mutations.	Schubert D	Nature medicine	2014	PMID: 25329329
Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4.	Kuehn HS	Science (New York, N.Y.)	2014	PMID: 25213377
Impaired CD4 and CD8 effector function and decreased memory T cell populations in ICOS-deficient patients.	Takahashi N	Journal of immunology (Baltimore, Md. : 1950)	2009	PMID: 19380800
Homozygous loss of ICOS is associated with adult-onset common variable immunodeficiency.	Grimbacher B	Nature immunology	2003	PMID: 12577056
Pleiotropic defects in lymphocyte activation caused by caspase-8 mutations lead to human immunodeficiency.	Chun HJ	Nature	2002	PMID: 12353035
ICOS is critical for CD40-mediated antibody class switching.	McAdam AJ	Nature	2001	PMID: 11343122

Text-mined citations for this variant ...

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NC_000002.11:g.(?_201943606)_(204824322_?)del

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...