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]

Variant: NM_000212.3(ITGB3):c.197T>G (p.Leu66Arg)

CA8622895

695335 (ClinVar)

Gene: ITGB3
Condition: Glanzmann thrombasthenia
Inheritance Mode: Autosomal recessive inheritance
Link to MONDO
UUID: d9b94a86-212e-420f-98f5-7157dba80330
Approved on: 2023-12-19
Published on: 2023-12-19

HGVS expressions

NM_000212.3:c.197T>G
NM_000212.3(ITGB3):c.197T>G (p.Leu66Arg)
NC_000017.11:g.47283385T>G
CM000679.2:g.47283385T>G
NC_000017.10:g.45360751T>G
CM000679.1:g.45360751T>G
NC_000017.9:g.42715750T>G
NG_008332.2:g.34544T>G
ENST00000559488.7:c.197T>G
ENST00000559488.5:c.197T>G
ENST00000560629.1:c.162T>G
ENST00000571680.1:c.197T>G
NM_000212.2:c.197T>G
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Benign

Met criteria codes 1
BA1
Not Met criteria codes 4
PP4 PP3 BS2 BP4

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

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Platelet Disorders VCEP
The NM_000212.3(ITGB3):c.197T>G (p.Leu66Arg) 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 blood donor cohort (PMID: 32110192) but has not been reported in a GT patient. There is not consensus among computational evidence as to whether there is an effect on the gene or gene product. The variant occurs at a frequency in gnomAD v4.0.0 of 0.002756 (3252/1180038 alleles) in the European (non-Finnish) population, which is higher than the ClinGen PD VCEP BA1 threshold (>0.0024), and therefore meets this criterion (BA1). In summary this variant meets criteria for classification as Benign for Glanzmann thrombasthenia. GT-specific criteria applied: BA1.
Met criteria codes
BA1
The highest population minor allele frequency in gnomAD v4.0.0 is 0.002756 (3252/1180038 alleles) in the European (non-Finnish) population, which is higher than the ClinGen PD VCEP threshold (>0.0024), and therefore meets this criterion (BA1).
Not Met criteria codes
PP4
Has been observed heterozygous in 5 unrelated patients in an internal lab cohort with phenotypes not matching GT. No other ITGB3 variant or other explanation of disease was identified.
PP3
The REVEL score of 0.63 falls between the >0.7 PP4 threshold and the <0.25 BP4 threshold. No effect is predicted on splicing consensus sites by MaxEntScan or HSF however HSF does predict significant alteration of ESE / ESS motifs ratio.
BS2
The variant was identified in the sample cohort of blood and platelet donors in PMID: 32110192, however full genotypes were not provided and no clinical information was available to confirm that individuals are not affected with GT.
BP4
The REVEL score of 0.63 falls between the >0.7 PP4 threshold and the <0.25 BP4 threshold. No effect is predicted on splicing consensus sites by MaxEntScan or HSF however HSF does predict significant alteration of ESE / ESS motifs ratio.
Curation History
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