Abbreviations: PM1, pathogenic moderate; PM2, moderate piece of evidence for pathogenicity; PP2, supporting evidence using phenotype; PP3, supporting evidence for pathogenicity by computational (in silico) data; PS2, strong support for pathogenicity when the variants are de novo.

Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium.

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.

De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.

Located in a mutational hot spot and/or critical and well-established functional domain without benign variation.

Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).