The c.364A>G (p.Asn122Asp) variant in MAP2K1 was absent from gnomAD (PM2). It has been observed in 3 probands with clinical features of a RASopathy, including 1 de novo occurrence with maternity and paternity confirmed and 2 assumed de novo occurrences (PM2_VS; SCV000271240.2; Otto-von-Guericke-Universität Magdeburg internal communication; Invitae internal data, SCV000947966.1). Of these patients, 2 received a clinical diagnosis of either Noonan syndrome or cardiofaciocutaneous syndrome (PS4_Supporting). Of note, this variant was observed in 1 proband without clinical information who inherited it from a parent with unknown clinical status (GeneDx internal data). The c.364A>G (p.Asm122Asp) variant is located in MAP2K1, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant RASopathy based on RASopathy-specific ACMG/AMP criteria (PMID:29493581): PS2_VS, PS4_Supporting, PM2, PP2.