Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
Link to SEPIO compliant JSON-LD document
  • See Evidence submitted by expert panel for details.

Variant: NM_004958.3(MTOR):c.6644C>T (p.Ser2215Phe)

CA248393

156703 (ClinVar)

Gene: MTOR
Condition: overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes
Inheritance Mode: Autosomal dominant inheritance (mosaic)
Link to MONDO
UUID: d0c7e9a9-5d12-4d15-9442-bf75fb5f4d15

HGVS expressions

NM_004958.3:c.6644C>T
NM_004958.3(MTOR):c.6644C>T (p.Ser2215Phe)
NC_000001.11:g.11124516G>A
CM000663.2:g.11124516G>A
NC_000001.10:g.11184573G>A
CM000663.1:g.11184573G>A
NC_000001.9:g.11107160G>A
NG_033239.1:g.143036C>T
ENST00000361445.9:c.6644C>T
ENST00000361445.8:c.6644C>T
ENST00000376838.5:c.1259C>T
NM_004958.4:c.6644C>T
NM_001386500.1:c.6644C>T
NM_001386501.1:c.5396C>T
NM_004958.4(MTOR):c.6644C>T (p.Ser2215Phe)

Pathogenic

Met criteria codes 5
PM2_Supporting PS3_Supporting PS2 PS4 PP2
Not Met criteria codes 21
PM6 PM3 PM1 PM4 PM5 PVS1 BS2 BS4 BS3 BS1 BP5 BP7 BP2 BP3 BP4 BP1 BA1 PS1 PP4 PP1 PP3

Evidence Links 2

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Brain Malformations VCEP
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)
Met criteria codes
PM2_Supporting
absent from gnomAD
PS3_Supporting
Mutant alleles tested in S6 phosphorylation and neuronal cell culture experiments, the latter with reversal of phenotype upon everolimus treatment PubMed:27159400
PS2
Study designed using trios with filtration for absence in parents; subjects with FCD on neuroimaging, FCD2a on neuropathology, no mention of macroephaly. Mutant alleles tested in S6 phosphorylation and neuronal cell culture experiments, the latter with reversal of phenotype upon everolimus treatment. PubMed:27159400
2 IIb, 1 IIa with somatic mutations (no functional assay) PubMed:27830187
PS4
19 tumor samples in COSMIC
subjects with FCD on neuroimaging, FCD2a on neuropathology, no mention of macroephaly. Mutant alleles tested in S6 phosphorylation and neuronal cell culture experiments, the latter with reversal of phenotype upon everolimus treatment PubMed:27159400
2 IIb, 1 IIa with somatic mutations (no functional assay) PubMed:27830187
PP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Not Met criteria codes
PM6
Study designed using trios with filtration for absence in parents; subjects with FCD on neuroimaging, FCD2a on neuropathology, no mention of macroephaly. Mutant alleles tested in S6 phosphorylation and neuronal cell culture experiments, the latter with reversal of phenotype upon everolimus treatment. PubMed:27159400
2 IIb, 1 IIa with somatic mutations (no functional assay) PubMed:27830187
PM3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PVS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP7
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Approved on: 2022-02-12
Published on: 2022-02-12
The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.
¤ Powered by BCM's Genboree.