ClinVar Miner

Submissions for variant NM_004958.4(MTOR):c.6644C>T (p.Ser2215Phe)

dbSNP: rs587777894
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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Brain Malformations Variant Curation Expert Panel RCV001836737 SCV001949956 pathogenic Overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes 2022-02-12 reviewed by expert panel curation The c.6644C>T (NM_004958.4) variant in MTOR is a missense variant predicted to cause substitution of (p.Ser2215Phe). 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 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: 27159400) (PS3_Supporting). The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls (PS4; PMIDs: 27159400, 27830187 ; identified in 8 individuals with neuropathology confirmatory of a malformation of cortical development and 19 tumor samples in the literature and COSMIC). This variant has been confirmed de novo and has been identified with variable allelic fractions consistent with a post-zygotic event (PS2_Strong; PMIDs: 27159400, 27159400, 27830187). 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, PS3_P, PS4, PS2; 11 points (VCEP specifications version 1; Approved: 1/31/2021)
Baylor Genetics RCV000477713 SCV004183432 pathogenic Isolated focal cortical dysplasia type II 2023-11-27 criteria provided, single submitter clinical testing
James Howe Lab, University of Iowa Hospital and Clinics RCV000190281 SCV000191089 not provided not provided no assertion provided not provided
Database of Curated Mutations (DoCM) RCV000436863 SCV000506739 likely pathogenic Glioblastoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000419624 SCV000506740 likely pathogenic Papillary renal cell carcinoma type 1 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000430308 SCV000506741 likely pathogenic Neoplasm of the large intestine 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000439373 SCV000506742 likely pathogenic Malignant neoplasm of body of uterus 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000422164 SCV000506743 likely pathogenic Malignant melanoma of skin 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000429373 SCV000506744 likely pathogenic Papillary renal cell carcinoma, sporadic 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000440054 SCV000506745 likely pathogenic Neoplasm of uterine cervix 2016-05-31 no assertion criteria provided literature only
OMIM RCV000477713 SCV000564176 pathogenic Isolated focal cortical dysplasia type II 2020-09-16 no assertion criteria provided literature only

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