Total submissions: 7
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
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) |
Labcorp Genetics |
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 |
RCV000441728 | SCV000506722 | likely pathogenic | Glioblastoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000422764 | SCV000506723 | likely pathogenic | Breast neoplasm | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
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, |
RCV001260505 | SCV001437526 | pathogenic | CEBALID syndrome | 2020-09-01 | no assertion criteria provided | clinical testing | |
Undiagnosed Diseases Network, |
RCV003992287 | SCV004812044 | pathogenic | Macrocephaly-intellectual disability-neurodevelopmental disorder-small thorax syndrome | 2023-01-12 | no assertion criteria provided | clinical testing |