Table A2.

American College of Medical Genetics and Genomics criteria.

Code	Description
PVS1	Null variant (nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single or multiexon deletion) in a gene where LOF is a known mechanism of disease.
PS1	Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
PS2	De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
PS3	Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
BS1	Allele frequency is greater than expected for disorder.
PM1	Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation.
PM2	Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium.
PM3	For recessive disorders, detected in trans with a pathogenic variant
PM4	Protein length changes as a result of in-frame deletions/insertions in a non-repeat region or stop-loss variants.
PM5	Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
PP1	Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease.
PP2	Missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease.
PP3	Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.)
PP5	Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.
BP4	Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
BP6	Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.