Fig. 2.

Flowchart for the adapted PVS1 criterion for null variants: the FBN1 VCEP made minor modifications to the original PVS1 decision tree developed by ClinGen [29]. The only biological relevant transcript for FBN1 is NM_000138.5. Additionally, two aspects need to be taken into consideration: (1) NMD (nonsense-mediated mRNA decay) is predicted to occur when a stop codon is integrated in the FBN1 sequence, except for stop codons in the last exon or the last 50–55 nucleotides of the penultimate exon. (2) A critical region is defined using the same criteria as for the PM1 and PM1_Strong criteria