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]
  • 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_004958.3(MTOR):c.4448G>A (p.Cys1483Tyr)

CA16602888

376453 (ClinVar)

Gene: MTOR
Condition: cerebral malformation
Inheritance Mode: Autosomal dominant inheritance (mosaic)
Link to MONDO
UUID: 5cb91dd4-9595-443c-bc27-cd95f8241c6a
Approved on: 2021-02-01
Published on: 2021-09-27

HGVS expressions

NM_004958.3:c.4448G>A
NM_004958.3(MTOR):c.4448G>A (p.Cys1483Tyr)
NC_000001.11:g.11157173C>T
CM000663.2:g.11157173C>T
NC_000001.10:g.11217230C>T
CM000663.1:g.11217230C>T
NC_000001.9:g.11139817C>T
NG_033239.1:g.110379G>A
ENST00000703118.1:c.4448G>A
ENST00000703131.1:n.368G>A
ENST00000703140.1:c.4235G>A
ENST00000703141.1:c.4448G>A
ENST00000703142.1:c.*1278G>A
ENST00000361445.9:c.4448G>A
ENST00000361445.8:c.4448G>A
NM_004958.4:c.4448G>A
NM_001386500.1:c.4448G>A
NM_001386501.1:c.3200G>A
More

Pathogenic

Met criteria codes 6
PS4 PP2 PM2 PM5 PS2_Moderate PM1_Supporting
Not Met criteria codes 20
PVS1 PS1 PS3 PP1 PP3 PP4 BA1 PM6 PM3 PM4 BS1 BS4 BS3 BS2 BP5 BP7 BP4 BP3 BP1 BP2

Evidence Links 4

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Brain Malformations VCEP
The c.4448G>A p.C1483Y missense variant in the MTOR gene is previously reported in the literature and has been classified as PATHOGENIC. Testing of unaffected and affected tissue show variable allelic fractions consistent with a post-zygotic event (PMID: 28892148) (PS2_Moderate). This variant has been identified in 2 individuals with neuroimaging demonstrating at least one large cerebral hemisphere with cortical malformation(s), 1 individual with macrocephaly ( >=2 SD) and Developmental Delay or Intellectual disability without cortical malformations, it has been shown to demonstrate an increase cell growth phenotype in patient cell lines (PMID: 22729223), and was identified in at least 3 tumor samples in the literature and COSMIC (PMID: 22729223; PMID: 28892148; PMID: 25599672; PMID: 26619011) (PS4 Met_Strong). This variant is located in the MTOR kinase domain (PM1). This variant is absent from the Genome Aggregation Database (http://gnomad.broadinstitute.org) (PM2). This variant is located at the same amino acid as a pathogenic variant p.Cys1483Arg previously classified as pathogenic by the Brain Malformation Expert panel (PM5). This gene has a low rate of benign missense changes (PP2).
Met criteria codes
PS4
2 COSMIC tumor samples
Individual HME-1 with mosaic mutation. alternate allele frequency 14%; HME confirmed by MRI and neuropathology PubMed:25599672
Individual HME-1563: 5 y/o female with cortical dyslamination, cytomegalic neuron, ectopic neurons, hypomelanosis of Iso. Variant is somatic. Performed pathology PubMed:22729223
1 tumor sample PubMed:26619011
Patient P2, Spanish, 8 years old, male. Diagnosed with Smith-Kingsmore syndrome: Has megalencephaly/macrocephaly, ID, seizures, hypertelorism, open mouth appearance, smooth philtrum, hyperpigmented skin, strabismus, hypotonia. CNS image shows ventriculomegaly, gliosis, cavum vergae, periventricular venous malformation. "Mosaic in all studied tissues(blood, saliva, skin)" PubMed:28892148
PP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM2
absent from gnomAD
PM5
p.Cys1483Arg at the same amino acid position is Path., but not the same amino acid change
PS2_Moderate
Variant not found in blood sample but found in 8-36% of central operculum regions in indivdual with cortical dyslamination, cytomegalic neuron, ectopic neurons, and hypomelanosis of Iso PubMed:22729223
Patient P2 showed by NGS the mutant allele in 2% of blood sample, 11% in saliva 18% in hyperpigmented skin, and 28% in hypopigmented skin - confirmed by pyrosequencing PubMed:28892148
PM1_Supporting
kinase domain
Not Met criteria codes
PVS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS1
variant at the same amino acid position is Path., but not the same amino acid change
PS3
patient derived tissue
immunostained brain sections of patient with antibodies specific to the phosphorylated epitopse of S6 protein in a standard assay for activation of mTOR signaling. Cells with cytomegalic neurons were strongly labeled for phosphorylated S6 in DAB staining of HME brians. Concluded that the p.C1483Y variant increases mTOR signaling in affected brain regions PubMed:22729223
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
PP4
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
PM6
Variant not found in blood sample but found in 8-36% of central operculum regions in indivdual with cortical dyslamination, cytomegalic neuron, ectopic neurons, and hypomelanosis of Iso PubMed:22729223
Patient P2 showed by NGS the mutant allele in 2% of blood sample, 11% in saliva 18% in hyperpigmented skin, and 28% in hypopigmented skin - confirmed by pyrosequencing PubMed:28892148
PM3
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
BS1
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
immunostained brain sections of patient with antibodies specific to the phosphorylated epitopse of S6 protein in a standard assay for activation of mTOR signaling. Cells with cytomegalic neurons were strongly labeled for phosphorylated S6 in DAB staining of HME brians. Concluded that the p.C1483Y variant increases mTOR signaling in affected brain regions PubMed:22729223
BS2
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
BP4
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
BP1
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
Curation History
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