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.
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ACMG variant classification Platelet Disorders
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
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
•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
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
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
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
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