Variant: NM_004958.3(MTOR):c.4447T>C (p.Cys1483Arg)

CA16602264

374796 (ClinVar)

Gene: MTOR

Condition: cerebral malformation

Inheritance Mode: Autosomal dominant inheritance (mosaic)

UUID: 6ed31c33-11e4-468c-82e0-419ec860d576

Approved on: 2021-01-31

Published on: 2021-09-27

HGVS expressions

NM_004958.3:c.4447T>C
NM_004958.3(MTOR):c.4447T>C (p.Cys1483Arg)
NC_000001.11:g.11157174A>G
CM000663.2:g.11157174A>G
NC_000001.10:g.11217231A>G
CM000663.1:g.11217231A>G
NC_000001.9:g.11139818A>G
NG_033239.1:g.110378T>C
ENST00000703118.1:c.4447T>C
ENST00000703131.1:n.367T>C
ENST00000703140.1:c.4234T>C
ENST00000703141.1:c.4447T>C
ENST00000703142.1:c.*1277T>C
ENST00000361445.9:c.4447T>C
ENST00000361445.8:c.4447T>C
NM_004958.4:c.4447T>C
NM_001386500.1:c.4447T>C
NM_001386501.1:c.3199T>C

Pathogenic

• Met criteria codes: PS3_Supporting PS4 PP2 PM1_Supporting PS2_Moderate PM2 PM5

• Not Met criteria codes: BA1 BS1 BS4 BS3 BS2 BP5 BP7 BP4 BP3 BP1 BP2 PS1 PP1 PP3 PP4 PVS1 PM6 PM3 PM4

Expert Panel

Brain Malformations VCEP

Criteria Specification Information

Evidence submitted by expert panel

Brain Malformations VCEP

The c.4447T>C p.C1483R missense variant in the MTOR gene is previously reported in the literature and has been classified as PATHOGENIC. This variant has been shown to significantly increase phosphorylation levels in experiments with case and controls cells of similar isogenic backgrounds (PMID: 25799227, 24631838) (PS3_supporting). Testing of unaffected and affected tissue show variable allelic fractions consistent with a post-zygotic event (PMID: 25799227) (PS2_Moderate). This variant has been identified in 2 individuals with neuropathology confirmatory of a malformation of cortical development, 1 individual with neuroimaging demonstrating at least one large cerebral hemisphere with cortical malformation(s), 3 tumor samples in the literature and COSMIC (PMID: 28864461, 25799227) (PS4). This variant is located in the MTOR kinase domain(PM1). This variant is absent from the Genome Aggregation Database (http://gnomad.broadinstitute.org)

Met criteria codes

• PS4: 3 tumor samples in COSMIC
• PP2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM1_Supporting: located in the kinase domain
• PM2: absent from gnomAD
• PM5: C1483Y is a known pathogenic

Not Met criteria codes

• BA1: 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: 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
• 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
• 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: 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
• PVS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• 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