1-11114363-C-T

Variant names:

• chr1-11114363-C-T
• rs587777900
• NM_004958.4:c.7255G>A

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:5 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, 7 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 rank	MANE	Protein	UniProt
MTOR	NM_004958.4	c.7255G>A	p.Glu2419Lys	missense_variant	Exon 53 of 58	ENST00000361445.9	NP_004949.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTOR	ENST00000361445.9	c.7255G>A	p.Glu2419Lys	missense_variant	Exon 53 of 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:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1 Other:1

-

James Howe Lab, University of Iowa Hospital and Clinics

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Apr 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MTOR: PS2, PM2, PS4:Moderate, PP2, PP3 -

Overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes Pathogenic:1

Aug 04, 2024

Clinical Genomics Laboratory, Washington University in St. Louis

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

An MTOR c.7255G>A (p.Glu2419Lys) variant was identified at an allelic fraction consistent with somatic origin. This variant has been reported in several individuals with MTOR-related hypomelanosis of Ito with neurodevelopmental abnormalities (Carmignac V et al., PMID: 33833411; Vabres P et al., PMID: 26269266, Hadouiri N et al., PMID: 32805448; Bourgon N et al., PMID: 34170046) and has also been reported in multiple cancer cases in the cancer database COSMIC (COSMIC ID: COSV63869451). It is absent from the general population (gnomAD database v4.1.0), indicating it is not a common variant. This variant has been reported in the ClinVar database as a pathogenic variant by three submitters (ClinVar ID: 156709). The MTOR c.7255G>A (p.Glu2419Lys) variant resides within the kinase domain of MTOR that is defined as a critical functional domain (Carmignac V et al., PMID: 33833411; Mroske C et al., PMID: 26542245). Computational predictors indicate that the variant is damaging, evidence that correlates with impact to MTOR function. In support of this prediction, in vitro functional studies showed that the p.Glu2419Lys variant increased kinase activity, leading to elevated levels of phosphorylated AKT and p70S6K, indicating that this variant impacts protein function (Carmignac V et al., PMID: 33833411; Mroske C et al., PMID: 26542245; Yang H et al., PMID: 23636326). The MTOR gene is defined by the ClinGen's 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 (Lai A et al., PMID: 35997716). Based on available information and an internally developed protocol informed by the ACMG/AMP guidelines for variant interpretation and gene-specific practices from the ClinGen Criteria Specification Registry (Leon-Quintero FZ et al., PMID: 39434542), the MTOR c.7255G>A (p.Glu2419Lys) variant is classified as pathogenic. -

Inborn genetic diseases Pathogenic:1

Sep 24, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

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

-

Institute of Human Genetics, University Hospital of Duesseldorf

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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

- -

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;