rs587777893

chr1-11128107-G-Achr1-11128107-G-Cchr1-11128107-G-T

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_004958.4(MTOR):c.5930C>T(p.Thr1977Ile) 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1977K) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MTOR NM_004958.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 9.32

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 17 ACMG points.

• PM1: In a helix (size 7) in uniprot entity MTOR_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_004958.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-11128107-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 156702.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP2: Missense variant where missense usually causes diseases, MTOR
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.867
• PP5: Variant 1-11128107-G-A is Pathogenic according to our data. Variant chr1-11128107-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 584432.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MTOR	NM_004958.4	c.5930C>T	p.Thr1977Ile	missense_variant	43/58	ENST00000361445.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTOR	ENST00000361445.9	c.5930C>T	p.Thr1977Ile	missense_variant	43/58	1	NM_004958.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Apr 22, 2023	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects MTOR function (PMID: 27159400). 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. ClinVar contains an entry for this variant (Variation ID: 584432). This missense change has been observed in individuals with clinical features of MTOR-related conditions (PMID: 27159400, 30569621, 33833411). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 1977 of the MTOR protein (p.Thr1977Ile). -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 05, 2022	Published functional studies demonstrate constitutive activation of mTOR complex 1 and enlarged neuronal size (Mirzaa et al., 2016); Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 27159400, 30569621) -

MTOR-related megalencephaly and pigmentary mosaicism in skin Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Undiagnosed Diseases Network, NIH

May 11, 2018

A mosaic c.5930C>T (p.T1977I) pathogenic variant in the MTOR gene was detected in this individual (level of mosaicism 32%, 55 mutant and 117 reference reads). This variant has been previously reported as mosaic in 3 unrelated children with diffuse megalencephaly and pigmentary mosaicism in skin [PMID 27159400]. This variant has also been seen as mosaic in one internal patient with macrocephaly, overgrowth, and other similar symptoms. This individual has been reported in PMID: 30569621. -

Isolated focal cortical dysplasia type II Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Undiagnosed Diseases Network, NIH

Aug 23, 2019

- -

CEBALID syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Sep 01, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Benign	0.38	T;D
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Benign	0.085	D
MetaRNN	Pathogenic	0.87	D;D
MetaSVM	Uncertain	0.58	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-5.5	D;D
REVEL	Pathogenic	0.77
Sift	Uncertain	0.012	D;D
Sift4G	Uncertain	0.0070	D;D
Polyphen		1.0	.;D
Vest4		0.97
MutPred		0.45		.;Loss of ubiquitination at K1981 (P = 0.0481);
MVP		0.96
MPC		1.9
ClinPred		0.99	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.76
gMVP		0.83

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: rs587777893; hg19: chr1-11188164; COSMIC: COSV63868784; COSMIC: COSV63868784;