Evidence Repository - Clinical Genome Resources

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

Variant: NM_004958.4(MTOR):c.6644C>A (p.Ser2215Tyr)

CA16602587

376129 (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: 92c55e08-6866-4c47-ade5-8db428335094

HGVS expressions

NM_004958.4:c.6644C>A

NM_004958.4(MTOR):c.6644C>A (p.Ser2215Tyr)

NC_000001.11:g.11124516G>T

CM000663.2:g.11124516G>T

NC_000001.10:g.11184573G>T

CM000663.1:g.11184573G>T

NC_000001.9:g.11107160G>T

NG_033239.1:g.143036C>A

ENST00000361445.9:c.6644C>A

ENST00000361445.8:c.6644C>A

ENST00000376838.5:c.1259C>A

NM_004958.3:c.6644C>A

NM_001386500.1:c.6644C>A

NM_001386501.1:c.5396C>A

Pathogenic

PS3_Supporting PS4 PM2_Supporting PP2 PM5 PS2_Moderate

PS1 PVS1 BP5 BP7 BP2 BP3 BP4 BP1 BA1 PP4 PP1 PP3 PM6 PM3 PM1 PM4 BS2 BS4 BS3 BS1

Evidence Links 1

Expert Panel

Brain Malformations VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Brain Malformations VCEP

The c.6644C>A (NM_004958.4) variant in MTOR is a missense variant predicted to cause substitution of (p.Ser2215Tyr). 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). A different amino acid change (p.Ser2215Phe), at this locus, is classified as pathogenic for Overgrowth with or without cerebral malformations due to abnormalities in MTOR-pathway genes by the ClinGen BMEP (PM5). 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 (PMIDs: 20190810, 24631838, 28963468) (PS3_Supporting). The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls (PS4; PMID: 27830187, 29281825, 225401301, 26619011; identified in 5 individuals with neuropathology confirmatory of a malformation of cortical development, 1 individual with neuroimaging appearance consistent with a malformation of cortical development (without neuropathology), 1 individual with neuroimaging demonstrating at least one large cerebral hemisphere with cortical malformation(s), 15 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: 26018084). 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, PM5, PS3_P, PS4, PS2_M; 11 points (VCEP specifications version 1; Approved: 1/31/2021)

PS3_Supporting

variant shown to be activating in vitro and sensitive to rapamycin exposure PubMed:20190810

PS4

15 tumor samples in COSMIC https://cancer.sanger.ac.uk/cosmic/mutation/overview?id=20417

PM2_Supporting

absent from gnomAD

PP2