Total submissions: 1
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
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) |