Submissions for variant NM_004958.4(MTOR):c.4448G>A (p.Cys1483Tyr)

dbSNP: rs786205165

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Brain Malformations Variant Curation Expert Panel	RCV001836816	SCV001949984	pathogenic	Overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes	2022-02-17	reviewed by expert panel	curation	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)
Invitae	RCV001861478	SCV002212792	pathogenic	not provided	2022-03-19	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MTOR protein function. ClinVar contains an entry for this variant (Variation ID: 376453). This missense change has been observed in individual(s) with Smith-Kingsmore syndrome (PMID: 28892148). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 1483 of the MTOR protein (p.Cys1483Tyr).
Database of Curated Mutations (DoCM)	RCV000441728	SCV000506722	likely pathogenic	Glioblastoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000422764	SCV000506723	likely pathogenic	Breast neoplasm	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000433466	SCV000506724	likely pathogenic	Papillary renal cell carcinoma type 1	2016-05-31	no assertion criteria provided	literature only
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV001260505	SCV001437526	pathogenic	CEBALID syndrome	2020-09-01	no assertion criteria provided	clinical testing