The c.4A>G (p.Ser2Gly) variant in SHOC2 has been reported as a confirmed de novo occurrence in multiple patients with clinical features of a RASopathy (PS2_VeryStrong; Partners LMM, Institute of Human Genetics, Otto von Guericke University Magdeburg, APHP-Robert Debré Hospital internal data; GTR ID's: 21766, 506381, 28338; ClinVar SCV000062456.5, SCV000209051.10, SCV000263045.1 PMID 19684605, 21548061, 23918763, 22528146). The p.Ser2Gly variant has been identified in at least 5 independent occurrences in patients with clinical features of a RASopathy (PS4; Institute of Human Genetics, Otto von Guericke University Magdeburg, APHP-Robert Debré Hospital internal data GTR ID's: 506381, 28338; PMID: 25563136, 24458587). In vitro functional studies provide some evidence that the p.Ser2Gly variant may impact protein function (PS3; PMID: 19684605). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). The variant is located in the SHOC2 gene, 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 RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS2_VeryStrong, PS3, PS4, PM2, PP2.