Page 33 - Haematologica April 2020

RUNX1 variant curation
haematologica | 2020; 105(4)
875
continued from the previous page
ACMG/ AMP CC
Original ACMG/AMP rule summary
Specification
Stand Very alone strong
Strong
Moderate
Supporting
Comments
PM2
Absent from controls.
General rec
na na
na
Per original ACMG/AMP guidelines.
na
Variant must be completely absent from all population databases.
The mean coverage of RUNX1 in the population database used should be at least 20x.
PM3
For recessive disorders, detected in trans with a pathogenic variant.
na
FPD/AML is inherited in an autosomal dominant manner.
PM4
Protein length changes due
to in-frame deletions/insertions in a non-repeat region or stop-loss variants.
Gene- specific, strength
Other impacting deletion/
PM5
Missense change at AA residue where a different missense change determined to be pathogenic has been seen before.
Strength
na na
Missense change at the same residue where ≥2 different missense changes have previously been determined
Missense change at the same residue where a different missense change has previously been determined to be pathogenic.
Missense change at the same residue where a different missense change
see PS1
PM6
Assumed de novo (but without confirmation of maternity and paternity) in a patient with the disease and no family history.
Disease- specific, strength
na na
na
≥4 assumed de novo occurrences (without confirmation of maternity and paternity) in patients with the RUNX1-
2 or 3 assumed
see PS2
na na
na
In-frame
deletion/insertion in-frame
see PM1
to be pathogenic. PM5_strong cannot be applied together with PM1.
has previously been determined to be likely
Arg204.
at least one of the 13 hotspot residues Arg107, Lys110, Ala134, Arg162, Arg166, Ser167, Arg169, Gly170, Lys194, Thr196, Asp198, Arg201, Arg204
insertion impacting residues 105-204 within the RHD.
pathogenic.
de novo
occurrences (without confirmation of maternity and paternity) in patients with the RUNX1-
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