Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
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Variant: NM_000212.3:c.662C>T

CA8623017

1210206 (ClinVar)

Gene: ITGB3
Condition: Glanzmann thrombasthenia
Inheritance Mode: Autosomal recessive inheritance
Link to MONDO
UUID: 9cead35a-93be-4ac1-8655-ea2bc266eea0
Approved on: 2024-04-16
Published on: 2024-04-16

HGVS expressions

NM_000212.3:c.662C>T
NC_000017.11:g.47286307C>T
CM000679.2:g.47286307C>T
NC_000017.10:g.45363673C>T
CM000679.1:g.45363673C>T
NC_000017.9:g.42718672C>T
NG_008332.2:g.37466C>T
ENST00000696963.1:c.662C>T
ENST00000559488.7:c.662C>T
ENST00000559488.5:c.662C>T
ENST00000560629.1:c.627C>T
ENST00000571680.1:c.662C>T
NM_000212.2:c.662C>T

Uncertain Significance

Met criteria codes 1
PM2_Supporting
Not Met criteria codes 5
PS3 PP4 PP3 PM3 BP4

Evidence Links 1

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen Platelet Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 2.1

PDF
Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Platelet Disorders VCEP
The ITGB3 missense variant NM_000212.2:c.662C>T replaces the threonine residue with a methionine residue (p.Thr221Met). This variant has been observed in heterozygosity in an individual suspected to have Glanzmann's thrombasthenia (GT) (GT-72 in PMID: 30792900), however sufficient information to confirm if the individual's phenotype is specific for GT was not provided and a second ITGB3 variant was not identified. In silico tools do not predict the variant is damaging to protein function or mRNA splicing. The highest population minor allele frequency in gnomAD v4.0.0 is 0.00007810 (5/64024alleles) in the European (Finnish) population, which is lower than the ClinGen PD VCEP threshold (<0.0001; PM2_Supporting). In summary, this variant is of uncertain significance and lacks sufficient evidence to be classified as pathogenic or benign for GT. GT-specific criteria applied: PM2_supporting.
Met criteria codes
PM2_Supporting
The highest population minor allele frequency in gnomAD v4.0.0 is 0.00007810 (5/64024alleles) in the European (Finnish) population, which is lower than the ClinGen PD VCEP threshold (<0.0001; PM2_Supporting).
Not Met criteria codes
PS3
This variant has been investigated as the molecular basis for the platelet-specific Vaa antigen implicated in severe fetal maternal alloimmune thrombocytopenia. PMID: 18484951 reported functional studies of this variant, but they are related to examining the reactivity of this human platelet antigen (HPA‐17bw) and are not applicable as PS3 evidence for the relationship of this variant to Glanzmann thrombasthenia.
Calmodulin-tagged soluble recombinant β3 encoding this variant was expressed in Drosophila S2 cells and found to react with maternal Vaa antiserum. PubMed:18484951
PP4
This variant has been observed in an individual with a previous history of type III or variant Glanzmann thrombasthenia (GT-72 in PMID: 30792900), but sufficient phenotypic details, platelet aggregation information, and protein surface expression information were not provided to apply PP4 at any strength level.
PP3
The REVEL score for this variant is 0.633, below the VCEP-established threshold of ≥0.7 to apply PP3 and above the VCEP-established threshold of <0.25 to apply BP4. Additionally, splice predictors (SpliceAI and NNSPLICE) do not predict a damaging effect on splicing.
PM3
This variant was identified in heterozygosity in one individual (GT-72, PMID: 30792900) with no second ITGB3 variant identified. PM3 could not be applied at any strength level for this heterozygous occurrence.
BP4
See explanation for PP3.
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