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.5930C>A (p.Thr1977Lys)

CA248390

156702 (ClinVar)

Gene: MTOR
Condition: overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes
Inheritance Mode: Autosomal dominant inheritance (mosaic)
UUID: 9187950f-2c32-459c-b678-3bd146dec7ec
Approved on: 2022-02-12
Published on: 2022-02-12

HGVS expressions

NM_004958.3:c.5930C>A
NM_004958.3(MTOR):c.5930C>A (p.Thr1977Lys)
NC_000001.11:g.11128107G>T
CM000663.2:g.11128107G>T
NC_000001.10:g.11188164G>T
CM000663.1:g.11188164G>T
NC_000001.9:g.11110751G>T
NG_033239.1:g.139445C>A
ENST00000703118.1:c.*1305C>A
ENST00000703131.1:n.1734C>A
ENST00000703139.1:c.567C>A
ENST00000703140.1:c.5717C>A
ENST00000703141.1:c.*1250C>A
ENST00000703142.1:c.*2760C>A
ENST00000361445.9:c.5930C>A
ENST00000361445.8:c.5930C>A
ENST00000376838.5:c.545C>A
NM_004958.4:c.5930C>A
NM_001386500.1:c.5930C>A
NM_001386501.1:c.4682C>A
More

Pathogenic

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

Evidence Links 3

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Brain Malformations VCEP
The c.5930C>A (NM_004958.4) variant in MTOR is a missense variant predicted to cause substitution of (p.Thr1977Lys). 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 control cells of similar isogenic backgrounds indicating that this variant impacts protein function (PMID: 24631838) (PS3_Supporting). The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls (PS4; PMIDs w/ phenotypes). Testing of unaffected and affected tissue show variable allelic fractions consistent with a post-zygotic event (PS2_Moderate; PMID: 25799227). 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
PM1_Supporting
kinase domain
PS4
5 tumor samples in COSMIC

PS2_Moderate
PP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS3_Supporting
PM2_Supporting
absent from gnomAD
Not Met criteria codes
PVS1
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
BA1
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
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
PM6
BS2
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
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
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
Curation History
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