1-11114363-C-T

Position:

• chr1-11114363-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_004958.4(MTOR):​c.7255G>A​(p.Glu2419Lys) 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MTOR NM_004958.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4 O:1
• Conservation: PhyloP100: 7.54

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]

ACMG classification

Verdict is Pathogenic. Variant got 16 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, 6 uncertain in NM_004958.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.944
• PP5: Variant 1-11114363-C-T is Pathogenic according to our data. Variant chr1-11114363-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 156709.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MTOR	NM_004958.4	c.7255G>A	p.Glu2419Lys	missense_variant	53/58	ENST00000361445.9	NP_004949.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MTOR	ENST00000361445.9	c.7255G>A	p.Glu2419Lys	missense_variant	53/58	1	NM_004958.4	ENSP00000354558.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1 Other:1

not provided, no classification provided	literature only	James Howe Lab, University of Iowa Hospital and Clinics	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	MTOR: PS2, PM2, PS4:Moderate, PP2, PP3 -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 24, 2024

The c.7255G>A (p.E2419K) alteration is located in exon 53 (coding exon 52) of the MTOR gene. This alteration results from a G to A substitution at nucleotide position 7255, causing the glutamic acid (E) at amino acid position 2419 to be replaced by a lysine (K). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been determined to be the result of a de novo mutation or germline mosaicism in two individuals and heterozygous in two individuals with infantile onset seizures, developmental delay, hemimegalencephaly, ventriculomegaly, linear hypomelanosis, left overgrowth, and/or dysmorphic facial features (Garcia, 2020; Carmignac, 2021; Fu, 2022) This amino acid position is highly conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek, 2016; Firth, 2009). Functional studies suggest a gain of function effect; however, additional evidence is needed to confirm this finding (Urano, 2007; Wagle, 2014). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

CEBALID syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Sep 01, 2020

- -

Macrocephaly-intellectual disability-neurodevelopmental disorder-small thorax syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

not provided

Institute of Human Genetics, University Hospital of Duesseldorf

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.48	T;D;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D;D;D
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.94	D;D;D
MetaSVM	Pathogenic	0.84	D
MutationAssessor	Pathogenic	3.4	.;M;.
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-4.0	D;D;D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.033	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.88
MutPred		0.80		.;Gain of ubiquitination at E2419 (P = 0.0276);.;
MVP		0.96
MPC		2.6
ClinPred		1.0	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.93
gMVP		0.98

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

Other links and lift over

dbSNP: rs587777900; hg19: chr1-11174420; COSMIC: COSV63869451;