Evidence Repository - Clinical Genome Resources

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.437T>C

CA400021960

1210169 (ClinVar)

Gene: ITGB3

Condition: Glanzmann thrombasthenia

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: f8d813fb-e78f-4f0b-8cda-3f8f130b708d

Approved on: 2024-04-16

Published on: 2024-04-16

HGVS expressions

NM_000212.3:c.437T>C

NC_000017.11:g.47284518T>C

CM000679.2:g.47284518T>C

NC_000017.10:g.45361884T>C

CM000679.1:g.45361884T>C

NC_000017.9:g.42716883T>C

NG_008332.2:g.35677T>C

ENST00000696963.1:c.437T>C

ENST00000559488.7:c.437T>C

ENST00000559488.5:c.437T>C

ENST00000560629.1:c.402T>C

ENST00000571680.1:c.437T>C

NM_000212.2:c.437T>C

Uncertain Significance

PM2_Supporting PP3 PM3_Supporting

PP4

Evidence Links 0

Expert Panel

Platelet Disorders VCEP

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_000212.3:c.437T>C replaces the leucine residue with a proline residue (p.Leu146Pro). The highest population minor allele frequency in gnomAD v4.0.0 is 8.993e-7 (1/1112008 alleles) in the European (non-Finnish) population, which is lower than the ClinGen PD VCEP threshold (<0.0001; PM2_Supporting). This variant has been observed in homozygosity (PM3_supporting) in an individual suspected to have Glanzmann's thrombasthenia (GT) (GT-76 in PMID: 30792900), however sufficient information to confirm if the individual's phenotype is specific for GT was not provided. In silico tools predict the variant is damaging to protein function (REVEL score 0.985; PP3). 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, PM3_supporting, PP3.

PM2_Supporting

The highest population minor allele frequency in gnomAD v4.0.0 is 8.993e-7 (1/1112008 alleles) in the European (non-Finnish) population, which is lower than the ClinGen PD VCEP threshold (<0.0001; PM2_Supporting).

PP3

REVEL score of 0.985 is above the >0.7 threshold to support a deleterious effect.

PM3_Supporting

This variant has been observed in homozygosity in one individual (Patient GT-76, PMID: 30792900), sufficient to apply PM3_supporting.

PP4

This variant has been observed in an individual with a previous history of type I Glanzmann thrombasthenia (GT-76 in PMID: 30792900), but sufficient platelet aggregation information was not provided to apply PP4 at any strength level.

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