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(ITGB3):c.754A>G (p.Ile252Val)

CA8623033

695644 (ClinVar)

Gene: ITGB3

Condition: Glanzmann thrombasthenia

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: d5f34307-829e-4e58-a8ad-8ec108021816

HGVS expressions

NM_000212.3:c.754A>G

NM_000212.3(ITGB3):c.754A>G (p.Ile252Val)

NC_000017.11:g.47286399A>G

CM000679.2:g.47286399A>G

NC_000017.10:g.45363765A>G

CM000679.1:g.45363765A>G

NC_000017.9:g.42718764A>G

NG_008332.2:g.37558A>G

ENST00000696963.1:c.754A>G

ENST00000559488.7:c.754A>G

ENST00000559488.5:c.754A>G

ENST00000560629.1:c.719A>G

ENST00000571680.1:c.754A>G

NM_000212.2:c.754A>G

Uncertain Significance

BS1

BP4 BP5 BS2 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 NM_000212.3(ITGB3):c.754A>G (p.Ile252Val) missense variant was observed by Illumina as part of a predisposition screen in an ostensibly healthy population and has been reported in the literature in a control cohort (PMID: 29232918) but has not been reported in a GT patient. There is not consensus among computation evidence as to whether there is an effect on the gene or gene product. The variant occurs at an allele frequency greater than expected for the disorder, with the highest continental population frequency in gnomADv4.0.0 is 0.001999 (120/60028 alleles) in the Admixed American population. This is above the threshold of >0.00158 for BS1 but below the BA1 threshold of 0.0024. In summary there is insufficient evidence resulting in a classification of Uncertain Significance. GT-specific criteria applied: BS1.

BS1

The highest continental population frequency in gnomADv4.0.0 is 0.001999 (120/60028 alleles) in the Admixed American population. This is above the threshold of >0.00158 for BS1 but below the BA1 threshold of 0.0024.

BP4

The REVEL score of 0.476 falls between the >0.7 PP3 threshold and the <0.25 BP4 threshold. No effect is predicted on splicing consensus sites by MaxEntScan, HSF, or SpliceAI. The nucleotide is highly conserved (phyloP score 6.288).

BP5

Specified as not applicable for GT. This variant was identified heterozygous in two probands (cases 3 and 6) with thrombocytopenia, found to result from an E527K SRC, which segregated with thrombocytopenia in 5 additional family members (PMID: 35349645).

BS2

The variant was identified in the control population in PMID: 29232918, however full genotypes were not provided and no clinical information was available to confirm that individuals are not affected with GT. Additionally, there is one homozygote in gnomAD but again no clinical information is available.

PP4

5 individuals heterozygous for this variant were identified in an inherited platelet disorders cohort, however their phenotypes were not GT.

Approved on: 2024-05-02

Published on: 2024-05-03

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