The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • No ClinVar Id was directly found from the curated document


Variant: NM_000419.5:c.2941C>T

CA399790399

Gene: ITGA2B
Condition: Glanzmann thrombasthenia
Inheritance Mode: Autosomal recessive inheritance
UUID: bd273211-4fdf-46e1-b2f1-940633954c3d
Approved on: 2023-01-17
Published on: 2023-02-15

HGVS expressions

NM_000419.5:c.2941C>T
NC_000017.11:g.44374661G>A
CM000679.2:g.44374661G>A
NC_000017.10:g.42452029G>A
CM000679.1:g.42452029G>A
NC_000017.9:g.39807555G>A
NG_008331.1:g.19845C>T
ENST00000262407.6:c.2941C>T
ENST00000648408.1:n.2372C>T
ENST00000262407.5:c.2941C>T
ENST00000587295.5:n.253+1172C>T
ENST00000588098.1:n.35C>T
ENST00000592462.5:n.2452C>T
NM_000419.3:c.2941C>T
NM_000419.4:c.2941C>T

Pathogenic

Met criteria codes 5
PVS1_Moderate PP4_Moderate PM2_Supporting PS3 PP1
Not Met criteria codes 1
PM3

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 c.2941C>T (p.Gln981Ter) variant in exon 28 is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 28 and is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. Additionally, In two siblings, it has been shown that this mutation results in exon 28 being spliced out of the final protein product (PMID: 8111043, PVS1_Moderate). Surface expression of αIIb measured by Western blot in COS-1 cells transiently co-transfected with c.2941C>T (p.Gln981Ter) αIIb and wild type αIIb showed decreased expression at 0% of WT levels, indicating that this variant impacts protein function (PMID: 1932748)(PS3). At least two patients (Patient 1 and Patient 2 from PMID:8111043) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia. Additionally, αIIbβ3 surface expression was reduced to 0% as measured by flow cytometry. However, ITGA2B and ITGB3 were not reported to be sequenced across all exons and intron/exon boundaries (PP4_Moderate). This variant has also been reported to segregate with Glanzmann thrombasthenia in the proband (confirmed by bleeding phenotype and platelet aggregometry) plus the proband's affected sister. The c.2941C>T (p.Gln981Ter) variant is inherited from the patients' father and an unspecified ITGA2B variant is inherited from their mother (PP1_Supporting, PMID: 8111043). Finally, this variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1, PS3, PP4_Moderate, PP1 and PM2_Supporting (VCEP specifications version 2.1).
Met criteria codes
PVS1_Moderate
The c.2941C>T (p.Gln981Ter) variant in exon 28 is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 28 of 30 and is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. In two siblings, it has been shown that this mutation results in alternative splicing in which exon 28 is skipped (PMID: 8111043, PVS1_Moderate).
PP4_Moderate
At least two patients (Patient 1 and Patient 2 PMID:8111043 with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia. Additionally, αIIbβ3 surface expression was reduced to 0% as measured by flow cytometry. However, ITGA2B and ITGB3 were not reported to be sequenced across all exons and intron/exon boundaries (PP4_Moderate).
PM2_Supporting
This variant is absent from gnomAD v2.1.1 (PM2_Supporting).
PS3
Surface expression of αIIb measured by Western blot in COS-1 cells transiently co-transfected with an (exon 28 null variant) αIIb and wild type αIIb showed decreased expression at 0% of WT levels, indicating that this variant impacts protein function (PMID: 1932748)(PS3).
PP1
The variant has been reported to segregate with Glanzmann thrombasthenia in the proband (confirmed by bleeding phenotype and platelet aggregometry) plus the proband's affected sister. The c.2941C>T (p.Gln981Ter) is inherited from the patients' father and an unspecified ITGA2B variant is inherited from their mother (PP1_Supporting, PMID: 8111043).
Not Met criteria codes
PM3
This variant has been detected in at least 1 proband with Glanzmann thrombasthenia. This individual was compound heterozygous for this variant and a variant that were confirmed in trans by family testing (paternal variant = c.2941C>T (p.Gln981Ter) and maternal allele is unspecified (PMID: 8111043). PM3 is not met.
The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.
¤ Powered by BCM's Genboree.