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Please note this is a beta version of the ClinGen Evidence Repository. This resource is intended to provide access to variant level evidence used and applied by ClinGen Variant Curation Expert Panels in the classification of variants. In this beta version, the evidence is limited to curation notes and referenced literature (PMIDs).

For general information about ClinGen Expert Panels and Variant Curation please visit: Clinical Domain Working Groups. For specific inquiries regarding a variant classification or evidence curation (e.g. population database queried, segregation counts or other evidence used) or to submit general comments about the evidence repo, please email us.

The resource is undergoing updates and tesing. Should you encounter any issues regarding the data displayed, lack of functionality or other problems, please let us know so we can rectify these accordingly. Your help in this regard is greatly appreciated.

ACMG variant classification Platelet Disorders

Benign
Pathogenic
Stand Alone
Strong
Supporting
Supporting
Moderate
Strong
Very Strong
Population Data

Frequency cutoff of 0.24% (>0.0024 at 99.99% CI w/subpopulation w/min of 5 alleles). BA1

>1 homozygote who is unaffected proven with at least aggregometry. BS2

Frequency cutoff of 0.158% (>0.00158 at 99.99% CI w/subpopulation w/min of 5 alleles) BS1

Prevalence <1/10,000 (<0.0001) alleles in gnomAD. PM2-Supporting

Rule does not apply due to rarity of disorder and lack of appropriate studies. PS4

Computational And Predictive Data

Use with no specification. BP7

REVEL score of < 0.25 BP4

Use with no specification BP3

Rule does not apply as truncating variants do not predominate and missense variants are a known cause of disease. BP1

Use at adjusted strength. PM5-Supporting

REVEL score of > 0.7 PP3

Use with no specification. PM5

Use with no specification. PM4

Use with no specification. PS1

Use decision tree as per SVI WG with specified “regions critical to protein function”. PVS1

Functional Data


•Must demonstrate normal aggregometry in a transgenic mouse model. OR * In a heterologous cell line, must demonstrate BOTH normal expression and normal protein function BS3

This rule does not apply because benign missense variants are not rare. PP2

In a model organism or heterologous cell line, significantly reduced surface protein expression (5
•25%). PS3-Moderate

Rule does not apply due to genes being highly polymorphic. PM1


•In a transgenic animal model, must demonstrate minimal to no function. OR * In a model organism or heterologous cell line, EITHER (A) when expression is normal or reduced, disruption of protein function must be demonstrated OR (B) Absent surface protein expression (<5%). PS3

Segregation Data

Variant not detected in an affected family member. BS4

Segregation in proband plus 1 affected relative.
•Affected relatives must have both variants identified in proband. PP1

Segregation in proband plus 2 affected relatives.
•Affected relatives must have both variants identified in proband. PP1-Moderate

Segregations in proband plus >2 affected relatives.
•Affected relatives must have both variants identified in proband. PP1-Strong

De novo Data

Use proposed SVI point recommendations.
•Only applicable when proband has a known pathogenic or likely pathogenic variant with the de novo variant PM6-Supporting

Use proposed SVI point recommendations.
•Only applicable when proband has a known pathogenic or likely pathogenic variant with the de novo variant PM6

Use proposed SVI point recommendations.
•Only applicable when proband has a known pathogenic or likely pathogenic variant with the de novo variant PS2-Moderate

Use proposed SVI point recommendations.
•Only applicable when proband has a known pathogenic or likely pathogenic variant with the de novo variant. PS2

Use proposed SVI point recommendations.
•Only applicable when proband has a known pathogenic or likely pathogenic variant with the de novo variant PM6-Strong

Use proposed SVI point recommendations.
•Only applicable when proband has a known pathogenic or likely pathogenic variant with the de novo variant. PM6-Very Strong

Allelic Data

Use as written for recessive variants (i.e. - variant must be observed in cis with a pathogenic variant) BP2

Use proposed SVI point recommendations. Both variants must be classified using ITGA2B/ITGB3 Rule Specifications. PM3-Supporting

Use proposed SVI point recommendations. Both variants must be classified using ITGA2B/ITGB3 Rule Specifications. PM3

Use proposed SVI point recommendations. Both variants must be classified using ITGA2B/ITGB3 Rule Specifications. PM3-Strong

Use proposed SVI point recommendations. Both variants must be classified using ITGA2B/ITGB3 Rule Specifications. PM3-Very Strong

Other Data

Do not use this rule as an individual can be a carrier of an unrelated pathogenic variant for a recessive disorder. BP5

Proband with clinical diagnosis of GT based on the presence of mucocutaneous bleeding and appropriate lab abnormalities. PP4-Moderate

Proband with clinical diagnosis of GT based on the presence of mucocutaneous bleeding and appropriate lab abnormalities. Full sequencing of both genes is required at this strength PP4-Strong

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.
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