VCV000627288.3 - ClinVar

NM_000419.5(ITGA2B):c.2569T>C (p.Cys857Arg)

Germline

Top reviewed classifications are shown here.

Submission summary:

2 submissions

2 submitters

1 condition

Reviewed by expert panel

Uncertain Significance

Jun 2024 by ClinGen Platel… FDA Recognized Database

for Glanzmann thrombasthenia

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000419.5(ITGA2B):c.2569T>C (p.Cys857Arg)

Variation ID: 627288 Accession: VCV000627288.3

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 17q21.31 17: 44375865 (GRCh38) [ NCBI UCSC ] 17: 42453233 (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	Sep 29, 2019	Jun 23, 2024	Jun 6, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000419.5(ITGA2B):c.2569T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_000419.5:c.2569T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000410.2:p.Cys857Arg	missense
NC_000017.11:g.44375865A>G
NC_000017.10:g.42453233A>G
NG_008331.1:g.18641T>C
LRG_479:g.18641T>C
LRG_479t1:c.2569T>C

... more HGVS ... less HGVS

Protein change

C857R

Other names

Canonical SPDI

NC_000017.11:44375864:A:G

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

dbSNP: rs1598376647 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.
ITGA2B		-	-	GRCh38 GRCh37	716	738

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.
Glanzmann thrombasthenia	Uncertain significance (2)	reviewed by expert panel	Jun 6, 2024	RCV000852093.3

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.
Uncertain Significance (Jun 06, 2024)	reviewed by expert panel (ClinGen Platelet ACMG Specifications v2-1) Method: curation	Glanzmann thrombasthenia (Autosomal recessive inheritance) Affected status: unknown Allele origin: germline	ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen FDA Recognized Database Accession: SCV001809863.2 First in ClinVar: Aug 27, 2021 Last updated: Jun 23, 2024	Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/1ba0c0d8-3f70-45c3-a98d-c8d377955761 Comment: The NM_000419.5(ITGA2B):c.2569T>C (p.Cys857Arg) missense variant is predicted deleterious with a REVEL score of 0.741 (PP3). The highest population minor allele frequency in gnomAD v4.0 is … (more) The NM_000419.5(ITGA2B):c.2569T>C (p.Cys857Arg) missense variant is predicted deleterious with a REVEL score of 0.741 (PP3). The highest population minor allele frequency in gnomAD v4.0 is 0.000007875 (6/761904 alleles) in the European (non-Finnish) population, which is lower than the ClinGen PD VCEP threshold (<0.0001; PM2_Supporting). It reported in one patient stated to have a disease of platelet function (PMID: 31064749) but information was insufficient or inconsistent to apply any evidence for this patient. Cys857Arg occurs at the same amino acid residue as Cys857Phe which is also classified by the PD-VCEP as VUS. In summary, based on the evidence available at this time, the variant is classified as uncertain significance. GT-specific criteria applied: PM2_supporting and PP3. (less)
Uncertain significance (Feb 01, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Glanzmann thrombasthenia 1 Affected status: yes Allele origin: unknown	NIHR Bioresource Rare Diseases, University of Cambridge Study: ThromboGenomics Accession: SCV000899634.1 First in ClinVar: Sep 29, 2019 Last updated: Sep 29, 2019	Publications: PubMed (1) PubMed: 31064749 Sex: male Ethnicity/Population group: European

Comment:

The NM_000419.5(ITGA2B):c.2569T>C (p.Cys857Arg) missense variant is predicted deleterious with a REVEL score of 0.741 (PP3). The highest population minor allele frequency in gnomAD v4.0 is 0.000007875 (6/761904 alleles) in the European (non-Finnish) population, which is lower than the ClinGen PD VCEP threshold (<0.0001; PM2_Supporting). It reported in one patient stated to have a disease of platelet function (PMID: 31064749) but information was insufficient or inconsistent to apply any evidence for this patient. Cys857Arg occurs at the same amino acid residue as Cys857Phe which is also classified by the PD-VCEP as VUS. In summary, based on the evidence available at this time, the variant is classified as uncertain significance. GT-specific criteria applied: PM2_supporting and PP3.

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
Diagnostic high-throughput sequencing of 2396 patients with bleeding, thrombotic, and platelet disorders.	Downes K	Blood	2019	PMID: 31064749
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/1ba0c0d8-3f70-45c3-a98d-c8d377955761	-	-	-	-

Text-mined citations for rs1598376647 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Jun 30, 2024

ClinVar Genomic variation as it relates to human health

NM_000419.5(ITGA2B):c.2569T>C (p.Cys857Arg)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1598376647 ...