NM_033360.4:c.183A>C (p.Gln61His) is a missense variant in KRAS, a gene in which gain-of-function missense variants cause RASopathies including Noonan syndrome and cardio-facio-cutaneous syndrome.¹ Multiple different pathogenic missense variants have been established at codon 61 in germline RASopathies (p.Gln61Arg and p.Gln61Lys), satisfying PM5 at Strong strength under the RASopathy VCEP. The Gln61His substitution is concordant with the known pathogenic direction of codon 61 changes which impair GTPase activity.² PP2 is applied at Supporting strength per VCEP specification, as PP2 is applicable to all RASopathy genes including KRAS.³ PP3 is applied at Supporting strength based on multiple computational lines of evidence: REVEL score 0.644 predicts a deleterious effect, residue 61 is a statistically significant mutational hotspot, and the variant is classified as Oncogenic (gain-of-function) by OncoKB.⁴ Variant-specific functional evidence from PMID:20147967 demonstrates that KRAS Q61H transforms NIH3T3 cells in focus formation assays and is present in the active GTP-bound conformation. PMID:25705018 shows Q61H produces a 5-6 fold increase in GTP-bound KRAS and promotes anchorage-independent growth in MCF10A isogenic cells. These studies provide strong functional support for a gain-of-function effect but do not meet the strict VCEP requirement for PS3 (must use VCEP-approved functional study publications).⁵ PM1 could not be applied because residue 61 falls in Switch II (residues 60-76), which is not explicitly listed in the available VCEP PM1 domain supplemental material (only P-loop 10-17 and Switch I 25-40 are listed). Human review is recommended as Switch II is a well-established critical functional domain and residue 61 is a documented mutational hotspot.⁶ PM2 is not met because the variant is present in gnomAD v2.1 at extremely low frequency (1/251,308 alleles) rather than being completely absent from all population databases as required by the VCEP.⁷ PVS1 is not applicable per VCEP designation and because this is a missense variant rather than a null variant. PS4, PS2, PM6, PP1, BS2, BS4, BP2, and BP5 could not be assessed due to absence of proband-level clinical data, de novo testing, or segregation analysis.⁸