rs587777893

Variant names:

• chr1-11128107-G-A
• rs587777893
• NM_004958.4:c.5930C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-11128107-G-A
• chr1-11128107-G-C
• chr1-11128107-G-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PM5 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:7
• 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 16 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.
• 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 rank	MANE	Protein	UniProt
MTOR	NM_004958.4	c.5930C>T	p.Thr1977Ile	missense_variant	Exon 43 of 58	ENST00000361445.9	NP_004949.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTOR	ENST00000361445.9	c.5930C>T	p.Thr1977Ile	missense_variant	Exon 43 of 58	1	NM_004958.4	ENSP00000354558.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Jul 05, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Oct 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of MTOR-related conditions (PMID: 27159400, 30569621, 33833411). ClinVar contains an entry for this variant (Variation ID: 584432). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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: 27159400). For these reasons, this variant has been classified as Pathogenic. -

Isolated focal cortical dysplasia type II Pathogenic:2

Aug 23, 2019

Undiagnosed Diseases Network, NIH

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 29, 2024

Clinical Genomics Laboratory, Washington University in St. Louis

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The MTOR c.5930C>T (p.Thr1977Ile) variant was identified at an allelic fraction consistent with somatic origin. This variant has been reported in multiple individuals with brain malformations (Handoko, M et al. PMID: 30569621; Mirzaa GM et al., PMID: 27159400; Cao Y et al. PMID: 31349857) and has also been reported as a somatic variant in multiple cancer cases in the cancer database COSMIC (COSMIC ID: COSV63868784). The MTOR c.5930C>T (p.Thr1977Ile) variant has been reported in the ClinVar database as a pathogenic variant in both a somatic and germline state by numerous submitters (ClinVar ID: 584432). It is absent from the general population database (gnomAD v4.1.0), indicating it is not a common variant. The MTOR c.5930C>T (p.Thr1977Ile) variant resides within the FAT domain of MTOR that is defined as a critical functional domain (Xu J et al., PMID: 27482884; Mirzaa GM et al., PMID: 27159400). Other variants in the same codon, (p.Thr1977Lys and p.Thr1977Arg), have been reported in individuals with brain malformations and are considered pathogenic (Baldassari S et al., PMID: 31444548; Xu J et al., PMID: 27482884; ClinVar ID's: 1296989 and 156702). 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.Thr1977Ile variant activates mTOR complex 1 (mTORC1) signaling (Mirzaa GM et al., PMID: 27159400). 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 (Leon-Quintero FZ et al., PMID: 39434542) and the ClinGen Brain Malformation Variant Curation Expert Panel (Lai A et al, PMID: 35997716), the MTOR c.5930C>T (p.Thr1977Ile) variant is classified as pathogenic. -

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

May 11, 2018

Undiagnosed Diseases Network, NIH

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

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

- -

MTOR-related disorder Pathogenic:1

Jan 01, 2024

Daryl Scott Lab, Baylor College of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS3, PS4, PM2, PP3 -

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
MutationAssessor	Uncertain	2.7	.;M
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;