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NM_000212.3(ITGB3):c.683G>A (p.Arg228His) AND Glanzmann thrombasthenia

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
Sep 5, 2024
Review status:
3 stars out of maximum of 4 stars
reviewed by expert panel
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV001580211.2

Allele description [Variation Report for NM_000212.3(ITGB3):c.683G>A (p.Arg228His)]

NM_000212.3(ITGB3):c.683G>A (p.Arg228His)

Gene:
ITGB3:integrin subunit beta 3 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
17q21.32
Genomic location:
Preferred name:
NM_000212.3(ITGB3):c.683G>A (p.Arg228His)
HGVS:
  • NC_000017.11:g.47286328G>A
  • NG_008332.2:g.37487G>A
  • NM_000212.3:c.683G>AMANE SELECT
  • NP_000203.2:p.Arg228His
  • LRG_481:g.37487G>A
  • NC_000017.10:g.45363694G>A
  • NC_000017.10:g.45363694G>A
Protein change:
R228H
Links:
dbSNP: rs756689153
NCBI 1000 Genomes Browser:
rs756689153
Molecular consequence:
  • NM_000212.3:c.683G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Glanzmann thrombasthenia
Synonyms:
PLATELET GLYCOPROTEIN IIb-IIIa DEFICIENCY; Thrombasthenia of Glanzmann and Naegeli; Glanzmann thrombasthenia type A; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0100326; MedGen: C0040015; Orphanet: 849; OMIM: PS273800

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Assertion and evidence details

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Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV001809844ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen
reviewed by expert panel

(ClinGen Platelet ACMG Specifications v2-1)		Uncertain Significance
(Sep 5, 2024) 		germlinecuration

Citation Link

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Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedcuration

Details of each submission

From ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen, SCV001809844.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

The p.Arg228His variant on ITGB3 gene is a missense variant that has been reported previously in the context of Glanzmann Thrombasthenia (PMID: 25728920). Multiple in silico tools predict this variant to be deleterious (REVEL score = 0.89; PP3). This variant is rare in large population databases with a MAF of 0.00008008 (6/74924) in the African subpopulation of gnomADv4.1 which is lower than the PD-VCEP threshold of <0.0001 (PM2_supporting). This variant has been reported in homozygosity in two symptomatic siblings who meet diagnostic criteria for GT phenotype (PMID: 25728920). However, the siblings are homozygous for both c.614+1G>T and Arg228His and while this splice variant is Likely Pathogenic an impact of the missense variant can not be excluded so this case has not been considered in the classification of this variant. This variant meets criteria for PP3 and PM2_supporting and is classified as a VUS.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Oct 13, 2024