The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC related information was provided by the message!
  • No CSPEC computed assertion could be determined for this classification!

  • See Evidence submitted by expert panel for details.

Variant: NM_004958.4(MTOR):c.4379T>C (p.Leu1460Pro)

CA16602588

376130 (ClinVar)

Gene: MTOR
Condition: overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes
Inheritance Mode: Autosomal dominant inheritance (mosaic)
UUID: 4aec1681-4a5e-413f-a6e7-6eb9120dcec6
Approved on: 2022-02-11
Published on: 2022-02-11

HGVS expressions

NM_004958.4:c.4379T>C
NM_004958.4(MTOR):c.4379T>C (p.Leu1460Pro)
NC_000001.11:g.11157242A>G
CM000663.2:g.11157242A>G
NC_000001.10:g.11217299A>G
CM000663.1:g.11217299A>G
NC_000001.9:g.11139886A>G
NG_033239.1:g.110310T>C
ENST00000703118.1:c.4379T>C
ENST00000703131.1:n.299T>C
ENST00000703140.1:c.4166T>C
ENST00000703141.1:c.4379T>C
ENST00000703142.1:c.*1209T>C
ENST00000361445.9:c.4379T>C
ENST00000361445.8:c.4379T>C
NM_004958.3:c.4379T>C
NM_001386500.1:c.4379T>C
NM_001386501.1:c.3131T>C
More

Pathogenic

Met criteria codes 6
PS3_Supporting PM2_Supporting PM1_Supporting PS2_Moderate PS4 PP2
Not Met criteria codes 20
PM6 PM3 PM5 PM4 BA1 PVS1 BS2 BS1 BS4 BS3 BP4 BP3 BP1 BP2 BP5 BP7 PS1 PP1 PP3 PP4

Evidence Links 6

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Brain Malformations VCEP
The c.4379T>C (NM_004958.4) variant in MTOR is a missense variant predicted to cause substitution of (p.Leu1460Pro). 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 controls 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: 26018084, 29281825, 27159400, 26831717; 3 individuals with neuropathology confirmatory of a malformation of cortical development, 1 individual with neuroimaging appearance consistent with a malformation of cortical development (without neuropathology), 4 tumor samples in the literature and COSMIC ). Testing of unaffected and affected tissue show variable allelic fractions consistent with a post-zygotic event (PS2_Moderate; PMID: 29281825, 26018084, 27159400). 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)
Met criteria codes
PS3_Supporting
PM2_Supporting
Absent from controls in Gnomad and Exac
PM1_Supporting
PS2_Moderate
Somatic in brain and blood

PS4
2 individuals is moderate evidence, 4 tumor samples in COSMIC

PP2
Z score is 7.89
Not Met criteria codes
PM6
PM3
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
PM4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BA1
Absent from controls in Gnomad and Exac
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
BS1
Absent from controls in Gnomad and Exac
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
BP4
Conflicting lines of evidence
BP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP1
Z score is 7.89
BP2
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
PS1
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
Conflicting lines of evidence
PP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
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