Submissions for variant NM_004958.4(MTOR):c.5930C>A (p.Thr1977Lys)

dbSNP: rs587777893

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Brain Malformations Variant Curation Expert Panel	RCV001836736	SCV001949953	pathogenic	Overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes	2022-02-12	reviewed by expert panel	curation	The c.5930C>A (NM_004958.4) variant in MTOR is a missense variant predicted to cause substitution of (p.Thr1977Lys). 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). This variant has been shown to significantly increase phosphorylation levels in experiments with case and control cells of similar isogenic backgrounds indicating that this variant impacts protein function (PMID: 24631838) (PS3_Supporting). The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls (PS4; PMIDs w/ phenotypes). Testing of unaffected and affected tissue show variable allelic fractions consistent with a post-zygotic event (PS2_Moderate; PMID: 25799227). In summary, this variant meets the criteria to be classified as 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, PS3_P, PS4, PS2_M; 10 points (VCEP specifications version 1; Approved: 1/31/2021)
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002272139	SCV002557694	pathogenic	Macrocephaly-intellectual disability-neurodevelopmental disorder-small thorax syndrome	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0101 - Gain-of-function is a known mechanism of disease for this gene. (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from threonine to lysine (exon 43). (N) 0251 - Variant is heterozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0502 - Missense variant with conflicting in silico predictions and/or uninformative conservation. (N) 0600 - Variant is located in an annotated domain or motif. (FAT domain; NCBI) (N) 0702 - Comparable variants have strong previous evidence for pathogenicity. (p.(Thr1977Ile) in patients with focal cortical dysplasia; ClinVar, PMID: 27159400). (P) 0802 - Moderate previous evidence of pathogenicity in unrelated individuals. (In 4 patients with focal cortical dysplasia; PMID: 25799227, 29281825, 31444548) (P) 0905 - No segregation evidence has been identified for this variant. (N) 1002 - Moderate functional evidence supporting abnormal protein function. Gain-of-function was demonstrated in animal models. (PMID: 27482884) (P) 1204 - Variant shown to be de novo in proband (parental status not tested but assumed). (P) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign
James Howe Lab, University of Iowa Hospital and Clinics	RCV000190280	SCV000191088	not provided	not provided		no assertion provided	not provided