ClinVar Miner

Submissions for variant NM_004958.4(MTOR):c.4375G>T (p.Ala1459Ser)

dbSNP: rs1644347846
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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Brain Malformations Variant Curation Expert Panel RCV001837033 SCV001949976 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.4375G>T (NM_004958.4) variant in MTOR is a missense variant predicted to cause substitution of (p.Ala1459Ser). 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 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_P; PMID: 27830187; 1 individual with neuroimaging appearance consistent with a malformation of cortical development (without neuropathology)). Testing of unaffected and affected tissue show variable allelic fractions consistent with a post-zygotic event (PS2_Moderate; PMID: 27830187). This variant has been observed cis with the variant [c.4379T>C, p.Leu1460Pro] (PMID: 27830187), (which is classified as pathogenic by the ClinGen BMEP) in an individual with features consistent with this disorder. (BP2). 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, PS4_P, PS2_M, BP2; 5 points (VCEP specifications version 1; Approved: 1/31/2021)

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