ClinVar Miner

Submissions for variant NM_004958.4(MTOR):c.1249A>G (p.Met417Val)

dbSNP: rs778680709
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Brain Malformations Variant Curation Expert Panel RCV001837035 SCV001949980 uncertain significance Overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes 2022-02-12 reviewed by expert panel curation The c.1249A>G (NM_004958.4) variant in MTOR is a missense variant predicted to cause substitution of (p.Met417Val). This variant is present in one individual in 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). 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; 2 points (VCEP specifications version 1; Approved: 1/31/2021)
Labcorp Genetics (formerly Invitae), Labcorp RCV002538663 SCV003468773 uncertain significance not provided 2022-10-19 criteria provided, single submitter clinical testing This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 417 of the MTOR protein (p.Met417Val). This variant is present in population databases (rs778680709, gnomAD 0.0009%). 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: 1296996). 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.

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