1-11130747-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_Very_Strong

The NM_004958.4(MTOR):c.5395G>A(p.Glu1799Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

MTOR
NM_004958.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:20O:1

Conservation

PhyloP100: 7.53

Publications

65 publications found

Variant links:

Genes affected

MTOR (HGNC:3942): (mechanistic target of rapamycin kinase) The protein encoded by this gene belongs to a family of phosphatidylinositol kinase-related kinases. These kinases mediate cellular responses to stresses such as DNA damage and nutrient deprivation. This kinase is a component of two distinct complexes, mTORC1, which controls protein synthesis, cell growth and proliferation, and mTORC2, which is a regulator of the actin cytoskeleton, and promotes cell survival and cell cycle progression. This protein acts as the target for the cell-cycle arrest and immunosuppressive effects of the FKBP12-rapamycin complex. Inhibitors of mTOR are used in organ transplants as immunosuppressants, and are being evaluated for their therapeutic potential in SARS-CoV-2 infections. Mutations in this gene are associated with Smith-Kingsmore syndrome and somatic focal cortical dysplasia type II. The ANGPTL7 gene is located in an intron of this gene. [provided by RefSeq, Aug 2020]

MTOR Gene-Disease associations (from GenCC):

macrocephaly-intellectual disability-neurodevelopmental disorder-small thorax syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Illumina, Orphanet, Labcorp Genetics (formerly Invitae), G2P
overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen

MTOR links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 14 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_004958.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.854

PP5

Variant 1-11130747-C-T is Pathogenic according to our data. Variant chr1-11130747-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 217823.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTOR	NM_004958.4 link	c.5395G>A	p.Glu1799Lys	missense_variant	Exon 39 of 58	ENST00000361445.9	NP_004949.1	P42345

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTOR	ENST00000361445.9 link	c.5395G>A	p.Glu1799Lys	missense_variant	Exon 39 of 58	1	NM_004958.4	ENSP00000354558.4		P42345

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

191474

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1428360

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

707194

African (AFR)

AF:

0.00

AC:

AN:

33052

American (AMR)

AF:

0.00

AC:

AN:

38650

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25450

East Asian (EAS)

AF:

0.00

AC:

AN:

38618

South Asian (SAS)

AF:

0.00

AC:

AN:

81934

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51204

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5722

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1094538

Other (OTH)

AF:

0.00

AC:

AN:

59192

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:20Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Macrocephaly-intellectual disability-neurodevelopmental disorder-small thorax syndrome

Pathogenic:8Other:1

Mar 22, 2021

Illumina Laboratory Services, Illumina

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The MTOR c.5395G>A (p.Glu1799Lys) variant is a missense variant that has been described in a heterozygous state in at least 12 individuals from seven unrelated families with features of Smith-Kingsmore syndrome (Baynam et al. 2015; Mroske et al. 2015; Mirzaa et al. 2016; Moosa et al. 2017; Gordo et al. 2018; Dobyns and Mirzaa 2019). An additional feature of multiple intestinal polyps was reported in one individual. In multiple cases, the variant was shown to occur de novo. In at least three families, the variant was found in multiple affected children despite not being detected in the parent's blood, suggesting gonadal mosaicism. The p.Glu1799Lys variant is not reported in the Genome Aggregation Database in a region of good sequence coverage, so the variant is presumed to be rare. Glu1799 is located in the FAT domain, which serves to regulate MTOR activity, and experiments in patient cells, human cell lines, and cultured rodent neurons have confirmed a gain-of-function effect of the p.Glu1799Lys variant (Grabiner et al. 2014; Baynam et al. 2015; Mirzaa et al. 2016). Based on the collective evidence, the p.Glu1799Lys variant is classified as pathogenic for Smith-Kingsmore syndrome. -

Jul 01, 2015

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Jan 01, 2019

Institute of Human Genetics, University of Leipzig Medical Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was identified as de novo. -

Sep 30, 2022

Eurofins-Biomnis

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 21, 2021

CENTOGENE GmbH and LLC - Guiding Precision Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 06, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: MTOR c.5395G>A (p.Glu1799Lys) results in a conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change. The frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. c.5395G>A has been observed in multiple individuals affected with Smith-Kingsmore Syndrome and majority of them are de novo for this variant (Mroske_2015, Mirzaa_2016, Tatton-Brown_2017). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and shows that this variant results in constitutive activation of MTOR protein (Mirzaa_2016). The following publications have been ascertained in the context of this evaluation (PMID: 27159400, 26542245, 28475857). ClinVar contains an entry for this variant (Variation ID: 217823). Based on the evidence outlined above, the variant was classified as pathogenic. -

GenomeConnect, ClinGen

Significance:not provided

Review Status:no classification provided

Collection Method:phenotyping only

Variant classified as Pathogenic and reported on 03-22-2021 by Illumina Clinical Services Laboratory. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Oct 19, 2020

Yale Center for Mendelian Genomics, Yale University

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Sep 24, 2023

3billion

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported (PMID: 23322780, 27482884, 21210909). Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.64 (>=0.6, sensitivity 0.68 and specificity 0.92)]. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000217823 /PMID: 25851998 /3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

not provided

Pathogenic:4

Dec 30, 2020

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PS4, PS3, PM6 -

Nov 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 30, 2021

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Functional studies indicate that E1799K results in an increase in mTOR pathway activity, suggesting a gain-of-function mechanism of disease (Baynam, et al., 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27739187, 27159400, 25851998, 26542245, 27513193, 27753196, 28892148, 28475857, 32581362, 33077954, 23636326, 24631838, 31441589, 31064327, 30764584, 30050716, 29296277, 27860216, 28007777, 24625776, 26432419) -

Jul 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1799 of the MTOR protein (p.Glu1799Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Smith‚ÄìKingsmore syndrome or MTOR-related megalencephaly and intellectual disability (PMID: 25851998, 26542245, 27159400, 27513193, 27753196, 28475857). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 217823). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MTOR protein function with a negative predictive value of 95%. Experimental studies have shown that this missense change affects MTOR function (PMID: 24631838, 25851998). For these reasons, this variant has been classified as Pathogenic. -

Intellectual disability

Pathogenic:2

Aug 02, 2021

Génétique des Maladies du Développement, Hospices Civils de Lyon

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

de novo variant, absent from gnomAD. Smith-Kingsmore syndrome -

Mar 30, 2020

Cambridge Genomics Laboratory, East Genomic Laboratory Hub, NHS Genomic Medicine Service

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Pathogenic:1

Feb 18, 2025

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.5395G>A (p.E1799K) alteration is located in exon 39 (coding exon 38) of the MTOR gene. This alteration results from a G to A substitution at nucleotide position 5395, causing the glutamic acid (E) at amino acid position 1799 to be replaced by a lysine (K). The MTOR c.5395G>A alteration was flagged as a low confidence call in the Genome Aggregation Database (gnomAD). This variant has been reported in multiple individuals with features consistent with Smith-Kingsmore syndrome; in at least one individual, it was determined to be de novo or the result of germline mosaicism (Baynam, 2015; Mroske, 2015; Moosa, 2017; Mirzaa, 2016; Poole, 2021; Ambry internal data). This amino acid position is highly conserved in available vertebrate species. The p.E1799 amino acid is located in the FAT domain of the MTOR protein, which binds to the kinase domain of the enzyme to negatively regulate MTOR activity (Yang, 2013). Structural modeling of the p.E1799K alteration suggests that this substitution destabilizes the FAT-kinase environment, leading to MTOR hyperactivation (Mroske, 2015). Functional analysis demonstrated that the p.E1799K alteration, which was originally identified in somatic tumor samples, results in activation of MTOR. Expression of MTOR with the p.E1799K alteration in HEK293 cells results in increased MTOR kinase activity towards AKT and 4E-Binding Protein 1, suggesting a gain-of-function effect (Grabiner, 2014). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Rare genetic intellectual disability

Pathogenic:1

Service de Génétique Moléculaire, Hôpital Robert Debré

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Intellectual disability, severe

Pathogenic:1

NIHR Bioresource Rare Diseases, University of Cambridge

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Isolated focal cortical dysplasia type II

Pathogenic:1

Jul 10, 2019

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

CEBALID syndrome

Pathogenic:1

Sep 01, 2020

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Isolated focal cortical dysplasia type II;C4225259:Macrocephaly-intellectual disability-neurodevelopmental disorder-small thorax syndrome

Pathogenic:1

Molecular Genetics Lab, CHRU Brest

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.28

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.31

T;D

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

D;D

M_CAP

Benign

0.057

MetaRNN

Pathogenic

0.85

D;D

MetaSVM

Benign

-0.46

MutationAssessor

Benign

2.0

.;M

PhyloP100

7.5

PrimateAI

Pathogenic

0.92

PROVEAN

Uncertain

-2.6

D;D

REVEL

Uncertain

0.64

Sift

Pathogenic

0.0

D;T

Sift4G

Pathogenic

0.0

D;T

Polyphen

0.88

.;P

Vest4

0.78

MutPred

0.77

.;Gain of MoRF binding (P = 0.0028);

MVP

0.91

MPC

2.0

ClinPred

0.99

GERP RS

5.5

Varity_R

0.61

gMVP

0.67

Mutation Taster

=17/83

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over