VCV000624587.3 - ClinVar

NM_005720.4(ARPC1B):c.64+1G>A

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, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

This haplotype includes the following variants

NM_005720.4(ARPC1B):c.64+1G>A - Variation ID 624614

NM_005720.4(ARPC1B):c.64+1G>A

Other names: -
Functional consequence: -
Links: -

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.
ARPC1B		-	-	GRCh38 GRCh37	292	318

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.
Platelet abnormalities with eosinophilia and immune-mediated inflammatory disease	Pathogenic (2)	criteria provided, single submitter	May 28, 2019	RCV000766124.2
not provided	Pathogenic (1)	criteria provided, single submitter	Jun 17, 2023	RCV003736902.2

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 28, 2019)	criteria provided, single submitter (Mendelics Assertion Criteria 2017) Method: clinical testing	Platelet abnormalities with eosinophilia and immune-mediated inflammatory disease Affected status: unknown Allele origin: unknown	Mendelics Accession: SCV001137429.1 First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019
Pathogenic (Jun 17, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV004551614.1 First in ClinVar: Feb 20, 2024 Last updated: Feb 20, 2024	Publications: PubMed (7) PubMed: 30254128‚ 30771411‚ 31031743‚ 16199547‚ 27965109‚ 28368018‚ 29127144 Comment: For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this … (more) For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Disruption of this splice site has been observed in individuals with clinical features of ARPC1B-related conditions (PMID: 30254128, 30771411, 31031743). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change affects a donor splice site in intron 2 of the ARPC1B gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ARPC1B are known to be pathogenic (PMID: 27965109, 28368018, 29127144). (less)
Pathogenic (Feb 28, 2019)	no assertion criteria provided Method: clinical testing	Platelet abnormalities with eosinophilia and immune-mediated inflammatory disease Affected status: yes Allele origin: germline	Laboratory of Pediatric Immunoinfectivology, Tor Vergata University Accession: SCV000897602.1 First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019	Publications: PubMed (1) PubMed: 30254128 DOI: 10.3389/fimmu.2019.00316 DOI: 10.3389/fimmu.2019.00316 Comment: CID (Combined Immunodeficiency) Reduced T cells, B+, reduced NK cells , reduced IgG and IgM, increased IgA and IgE Sex: male

Comment:

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Disruption of this splice site has been observed in individuals with clinical features of ARPC1B-related conditions (PMID: 30254128, 30771411, 31031743). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change affects a donor splice site in intron 2 of the ARPC1B gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ARPC1B are known to be pathogenic (PMID: 27965109, 28368018, 29127144).

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
Targeted NGS Platforms for Genetic Screening and Gene Discovery in Primary Immunodeficiencies.	Cifaldi C	Frontiers in immunology	2019	PMID: 31031743
A combined immunodeficiency with severe infections, inflammation, and allergy caused by ARPC1B deficiency.	Volpi S	The Journal of allergy and clinical immunology	2019	PMID: 30771411
T-cell defects in patients with ARPC1B germline mutations account for combined immunodeficiency.	Brigida I	Blood	2018	PMID: 30254128
Disruption of Thrombocyte and T Lymphocyte Development by a Mutation in ARPC1B.	Somech R	Journal of immunology (Baltimore, Md. : 1950)	2017	PMID: 29127144
Loss of the Arp2/3 complex component ARPC1B causes platelet abnormalities and predisposes to inflammatory disease.	Kahr WH	Nature communications	2017	PMID: 28368018
Combined immunodeficiency with severe inflammation and allergy caused by ARPC1B deficiency.	Kuijpers TW	The Journal of allergy and clinical immunology	2017	PMID: 27965109
Splicing in action: assessing disease causing sequence changes.	Baralle D	Journal of medical genetics	2005	PMID: 16199547

Text-mined citations for this variant ...

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_005720.4(ARPC1B):c.64+1G>A

Variant Details

NM_005720.4(ARPC1B):c.64+1G>A

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...