Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV001836902 | SCV001949986 | uncertain significance | Overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes | 2022-02-11 | reviewed by expert panel | curation | The c.5432G>T (NM_004958.4) variant in MTOR is a missense variant predicted to cause substitution of (p.Arg1811Leu). 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). This variant resides within the focal adhesion kinase targeting domain of MTOR that is defined as a critical functional domain by the ClinGen BMEP (PMIDs: 23322780, 27482884, 21210909) (PM1_Supporting). In summary, this variant meets the criteria to be classified as Uncertain significance 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, PM1_P; 3 points (VCEP specifications version 1; Approved: 1/31/2021) |
| Invitae | RCV000823157 | SCV000964005 | uncertain significance | not provided | 2023-02-22 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 1811 of the MTOR protein (p.Arg1811Leu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with MTOR-related conditions. ClinVar contains an entry for this variant (Variation ID: 664963). 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 not expected to disrupt MTOR protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |