ClinVar Miner

Submissions for variant NM_004958.4(MTOR):c.4468T>C (p.Trp1490Arg)

dbSNP: rs2100566800
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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 RCV001837032 SCV001949973 likely pathogenic Overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes 2022-02-11 reviewed by expert panel curation The c.4468T>C (NM_004958.4) variant in MTOR is a missense variant predicted to cause substitution of (p.Trp1490Arg). 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; PMID: 27830187 ; 1 individual with macrocephaly ( >=2 SD) and Developmental Delay or Intellectual disability without cortical malformations). This variant has been identified as a de novo occurrence with confirmed parental relationships (PS2_moderate; PMID: 27830187). In summary, this variant meets the criteria to be classified as Likely 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, PM1_P, PS4, PS2_M; 9 points (VCEP specifications version 1; Approved: 1/31/2021)

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