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]

Variant: NM_000419.4:c.889G>C

CA8603305

953005 (ClinVar)

Gene: ITGA2B (HGNC:3674)

Condition: Glanzmann thrombasthenia (MONDO:0010119)

Inheritance Mode: Autosomal recessive inheritance

UUID: 0e2ba47d-6962-4167-a1df-def62f5aa041

Approved on: 2024-09-05

Published on: 2024-09-30

HGVS expressions

NM_000419.4:c.889G>C

NC_000017.11:g.44384313C>G

CM000679.2:g.44384313C>G

NC_000017.10:g.42461681C>G

CM000679.1:g.42461681C>G

NC_000017.9:g.39817207C>G

NG_008331.1:g.10193G>C

ENST00000262407.6:c.889G>C

ENST00000648408.1:c.320G>C

ENST00000262407.5:c.889G>C

ENST00000589645.5:n.340G>C

ENST00000591990.5:n.434G>C

ENST00000592075.5:n.258G>C

ENST00000592226.5:n.129G>C

ENST00000592253.5:n.397G>C

NM_000419.3:c.889G>C

NM_000419.5:c.889G>C

Likely Pathogenic

PM3 PP4_Moderate PM2_Supporting PP1

BP4 PP3

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_000419.4:c.889G>C variant that results in the Ala297Pro amino acid change is seen in one unpublished homozygous GT individual with mild mucocutaneous bleeding symptoms and lack of platelet aggregation in response to ADP, collagen, U46619, AA and TRAP, but normal response to ristocetin (PP4_moderate). As well as their affected homozygous sibling (PP1). A second homozygous individual has also been reported (PM3; PMID: 32089034). The variant is reported in gnomADv4.1 at a frequency of 0.00004392 (4/91080 alleles) in the South Asian population, which is lower than the ClinGen PD VCEP threshold (<0.0001; PM2_Supporting). In summary, based on the available evidence at this time, the variant is classified as likely pathogenic for GT. GT-specific criteria applied: PM2_Supporting, PM3, PP1, and PP4_Moderate.

PM3

1 homozygous individual from internal laboratory data, with parents tested and found to be heterozygous for the variant and a second homozygote reported in PMID: 32089034 (1pt; PM3).

PP4_Moderate

One unpublished homozygous individual (from internal laboratory data) has mild mucocutaneous bleeding symptoms and lack of platelet aggregation in response to ADP, collagen, U46619, AA and TRAP, but normal response to ristocetin (PP4_moderate).

PM2_Supporting

The variant is reported in gnomADv4.1 at a frequency of 0.00004392 (4/91080 alleles) in the South Asian population, which is lower than the ClinGen PD VCEP threshold (<0.0001; PM2_Supporting).

PP1

The homozygous individual from internal laboratory data has a similarly affected sibling who is also homozygous for the variant. Segregation in 1 affected relative with phase confirmation meets criteria for PP1.

BP4

The computational predictor REVEL gives a score of 0.369, which is above the ClinGen PD VCEP PP3 threshold of <0.25.

PP3

The computational predictor REVEL gives a score of 0.369, which is below the ClinGen PD VCEP PP3 threshold of >0.7 and does not predict a damaging effect on ITGA2B function. And the computational splicing predictor SpliceAI indicated that the variant has no predicted impact on splicing.

Curation History

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