The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
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Variant: NM_000419.5:c.641T>G

CA399805518

1210203 (ClinVar)

Gene: ITGA2B
Condition: Glanzmann thrombasthenia
Inheritance Mode: Autosomal recessive inheritance
UUID: f1b331ac-2b12-493d-b88c-85af2b7fcb57
Approved on: 2024-08-20
Published on: 2024-08-20

HGVS expressions

NM_000419.5:c.641T>G
NC_000017.11:g.44385193A>C
CM000679.2:g.44385193A>C
NC_000017.10:g.42462561A>C
CM000679.1:g.42462561A>C
NC_000017.9:g.39818087A>C
NG_008331.1:g.9313T>G
ENST00000262407.6:c.641T>G
ENST00000648408.1:c.72T>G
ENST00000262407.5:c.641T>G
ENST00000589645.5:n.92T>G
ENST00000591990.5:n.3T>G
ENST00000592075.5:n.10T>G
ENST00000592226.5:n.10T>G
ENST00000592253.5:n.149T>G
ENST00000592944.1:n.323T>G
NM_000419.3:c.641T>G
NM_000419.4:c.641T>G
More

Likely Pathogenic

Met criteria codes 5
PM5 PP3 PM3_Supporting PP4_Moderate PM2_Supporting

Evidence Links 0

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 ITGA2B missense variant NM_000419.5:c.641T>G replaces the leucine residue with an arginine residue (p.Leu214Arg). This variant has been observed in homozygosity in a proband (Patient B, PMID: 26096001; PM3_supporting) with a phenotype specific for Glanzmann's thrombasthenia (GT), including a history of bleeding and impaired aggregation to at least two agonists, but normal or only mildly reduced agglutination with ristocetin (PP4_Moderate). This variant has not been reported in population databases, including gnomADv4.1.0 (PM2_supporting) and is predicted to be damaging by in silico tools (REVEL score 0.797; PP3). Furthermore, a different missense change at this amino acid residue (ITGA2B c.641T>C (p.Leu214Pro)) is classified as pathogenic by the Platelet Disorders VCEP (PM5). In summary, this variant meets criteria to be classified as likely pathogenic for GT. GT-specific criteria applied: PM2_supporting, PM3_supporting, PM5, PP4_moderate, PP3.
Met criteria codes
PM5
A different missense change at this amino acid residue (ITGA2B c.641T>C (p.Leu214Pro)) is classified as pathogenic by the Platelet Disorders VCEP.
PP3
The REVEL score for this variant is 0.797, exceeding the VCEP-established threshold of ≥ 0.7 to apply PP3.
PM3_Supporting
This variant was observed in homozygosity in one individual (Patient B in PMID: 26096001), earning 0.5 points and sufficient to apply PM3_supporting.
PP4_Moderate
All requirements for PP4_moderate are met (Patient B, PMID: 26096001): history of bleeding and impaired aggregation to at least two agonists, but normal or only mildly reduced agglutination with ristocetin.
PM2_Supporting
The highest population minor allele frequency in gnomAD v4.1.0 is 0.00001098 (1/91084 alleles) in the South Asian population, which is lower than the ClinGen PD VCEP threshold (<0.0001; PM2_Supporting).
Curation History
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