1-11130747-C-T

Position:

chr1-11130747-C-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2PP2PP3_ModeratePP5_Very_Strong

The ENST00000361445.9(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
ENST00000361445.9 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:17

Conservation

PhyloP100: 7.53

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 13 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), MTOR. . Gene score misZ 7.0206 (greater than the threshold 3.09). Trascript score misZ 9.4864 (greater than threshold 3.09). GenCC has associacion of gene with macrocephaly-intellectual disability-neurodevelopmental disorder-small thorax syndrome, overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes.

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 id is 217823.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-11130747-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MTOR	NM_004958.4 linkuse as main transcript	c.5395G>A	p.Glu1799Lys	missense_variant	39/58	ENST00000361445.9	NP_004949.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MTOR	ENST00000361445.9 linkuse as main transcript	c.5395G>A	p.Glu1799Lys	missense_variant	39/58	1	NM_004958.4	ENSP00000354558	P1

Frequencies

GnomAD3 genomes

Cov.:

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

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:17

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Macrocephaly-intellectual disability-neurodevelopmental disorder-small thorax syndrome

Pathogenic:6

Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 22, 2021	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. -
Pathogenic, no assertion criteria provided	literature only	Yale Center for Mendelian Genomics, Yale University	Oct 19, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	This variant was identified as de novo. -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins-Biomnis	Sep 30, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	Jun 21, 2021	- -

not provided

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 30, 2021	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Dec 30, 2020	PS4, PS3, PM6 -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 13, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2019	- -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 27, 2016

- -

Rare genetic intellectual disability

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Service de Génétique Moléculaire, Hôpital Robert Debré

- -

Intellectual disability, severe

Pathogenic:1

Pathogenic, no assertion criteria provided

research

NIHR Bioresource Rare Diseases, University of Cambridge

- -

Isolated focal cortical dysplasia type II

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Jul 10, 2019

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

Intellectual disability

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Génétique des Maladies du Développement, Hospices Civils de Lyon

Aug 02, 2021

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

CEBALID syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Sep 01, 2020

- -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Molecular Genetics Lab, CHRU Brest

- -

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

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

MutationTaster

Benign

1.0

D;D

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over