The c.4448G>A (NM_004958.4) variant in MTOR is a missense variant predicted to cause substitution of (p.Cys1483Tyr). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). MTOR, in which the variant was identified, is defined by the ClinGen Brain Malformations Expert Panel as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). A different amino acid change (p.Cys1483Arg), at this locus is classified as pathogenic for Overgrowth with or without cerebral malformations due to abnormalities in MTOR-pathway genes by the ClinGen BMEP (PM5). This variant resides within the kinase domain of MTOR that is defined as a critical functional domain by the ClinGen BMEP (PMIDs: 23322780, 27482884, 21210909) (PM1_Supporting). The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls (PS4; PMIDs: 22729223; 28892148; 25599672; 26619011; identified in 2 individuals with neuroimaging demonstrating at least one large cerebral hemisphere with cortical malformation(s), 1 individual with macrocephaly ( >=2 SD) and Developmental Delay or Intellectual disability without cortical malformations, it has been shown to demonstrate an increase cell growth phenotype in patient cell lines and at least 3 tumor samples in the literature and COSMIC). This variant has been confirmed de novo and has been identified with variable allelic fractions consistent with a post-zygotic event (PS2_Strong; PMID: 28892148). In summary, this variant meets the criteria to be classified as Pathogenic for mosaic autosomal dominant overgrowth with or without cerebral malformations due to abnormalities in MTOR-pathway genes based on the ACMG/AMP criteria applied, as specified by the ClinGen Brain Malformations Expert Panel: PM2_P, PP2, PM5, PM1_P, PS4, PS2; 13 points(VCEP specifications version 1; Approved: 1/31/2021)