Variant: NM_000212.3:c.1260G>A

CA8623200

996184 (ClinVar)

Gene: ITGB3

Condition: Glanzmann thrombasthenia

Inheritance Mode: Autosomal recessive inheritance

UUID: 914c2078-033b-4a0d-ab33-48fb8c7f9e8e

Approved on: 2023-11-02

Published on: 2023-11-03

HGVS expressions

NM_000212.3:c.1260G>A
NC_000017.11:g.47291088G>A
CM000679.2:g.47291088G>A
NC_000017.10:g.45368454G>A
CM000679.1:g.45368454G>A
NC_000017.9:g.42723453G>A
NG_008332.2:g.42247G>A
ENST00000559488.7:c.1260G>A
ENST00000559488.5:c.1260G>A
ENST00000560629.1:c.1225G>A
ENST00000571680.1:c.1260G>A
ENST00000573377.1:c.36G>A
NM_000212.2:c.1260G>A
NM_000212.3(ITGB3):c.1260G>A (p.Thr420=)

Likely Pathogenic

• Met criteria codes: PP3 PM4 PM3 PP4_Moderate PM2_Supporting

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

Evidence submitted by expert panel

Platelet Disorders VCEP

The ITGB3 synonymous variant NM_000212.3:c.1260G>A is predicted to lead to loss of the adjacent canonical splice donor and in vitro minigene assays and sequence analysis of patient mRNA suggest the variant results in the in frame deletion of exon 9 (PMID: 8878424; PM4). This variant has been observed in homozygosity in two individuals (Patient RS in PMID: 8878424 and GT50 in PMID: 25728920; PM3), at least one of which was reported to have a phenotype specific for Glanzmann's thrombasthenia (PMID: 25728920, GT50; PP4_moderate). Furthermore, the variant is rare in control population databases (MAF<1/10,000; PM2_supporting). In summary, this variant meets criteria to be classified as likely pathogenic for GT. GT-specific criteria applied: PM3, PM4, PM2_supporting, PP3, PP4_moderate.

Met criteria codes

• PP3: Multiple in silico splice tools predict this variant leads to loss of the adjacent canonical splice donor: SpliceAI (donor loss Δ score = 0.78), MaxEntScan (-62.61% change in score between wild type and variant), NNSPLICE (wild type donor site score = 0.97, variant donor site not recognized). However, both SpliceAI and NNSPLICE predict the gain of a splice donor 5 bp downstream that may be used as an alternate splice donor site (SpliceAI donor gain Δ score = 0.36; NNSPLICE donor site score = 0.45).
• PM4: In vitro minigene assays and sequence analysis of patient mRNA suggests the c.1260G>A variant results in the in frame skipping of exon 9 (PMID: 8878424), leading to a change in the overall length of the ITGB3 protein product.
• PM3: This variant has been reported in homozygosity in two individuals (Patient RS in PMID: 8878424 and GT50 in PMID: 25728920), who also carried a second common ITGB3 variant (initially reported as c.1143C>A, now referred to as c.1143A>C) in cis. This variant has also been observed in an additional report (CabGT-26 in PMID: 20020534) in combination with the c.1143C>A variant, however there was conflicting zygosity information and no information about phase confirmation. Each of the two homozygous occurrences scores 0.5 pts for a total of 1 point, sufficient to apply PM3.
• PP4_Moderate: At least one individual meets all requirements for PP4_moderate (PMID: 25728920, GT50): gingival bleeding and ecchymosis; total lack of platelet aggregation in response to physiologic agonists except normal response to ristocetin; direct sequencing of all coding regions of ITGA2B and ITGB3.
• PM2_Supporting: This variant is relatively rare in control population databases. It was observed in heterozygosity in four individuals in gnomAD v2.1.1 (MAF in African population: 0.00004005 (1/24968 alleles); overall allele frequency: 0.00001415 (4/282774 alleles)) and was not observed in gnomAD v3. This frequency is below the VCEP-established threshold of fewer than 1 in 10,000 alleles, meeting the criterion to apply PM2_supporting.