chr1-11157173-C-T

Position:

• chr1-11157173-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PS2_Moderate PM5 PS4 PM1_Supporting PP2 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.4448G>A (NM_004958.4) variant in MTOR is a missense variant predicted to cause substitution of (p.Cys1483Tyr). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). MTOR, in which the variant was identified, is defined by the ClinGen 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 (PP2). A different amino acid change (p.Cys1483Arg), at this locus is classified as pathogenic for Overgrowth with or without cerebral malformations due to abnormalities in MTOR-pathway genes by the ClinGen BMEP (PM5). This variant resides within the kinase domain of MTOR that is defined as a critical functional domain by the ClinGen BMEP (PMIDs: 23322780, 27482884, 21210909) (PM1_Supporting). The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls (PS4; PMIDs: 22729223; 28892148; 25599672; 26619011; identified in 2 individuals with neuroimaging demonstrating at least one large cerebral hemisphere with cortical malformation(s), 1 individual with macrocephaly ( >=2 SD) and Developmental Delay or Intellectual disability without cortical malformations, it has been shown to demonstrate an increase cell growth phenotype in patient cell lines and at least 3 tumor samples in the literature and COSMIC). This variant has been confirmed de novo and has been identified with variable allelic fractions consistent with a post-zygotic event (PS2_Strong; PMID:28892148). In summary, this variant meets the criteria to be classified as Pathogenic for mosaic autosomal dominant overgrowth with or without cerebral malformations due to abnormalities in MTOR-pathway genes based on the ACMG/AMP criteria applied, as specified by the ClinGen Brain Malformations Expert Panel: PM2_P, PP2, PM5, PM1_P, PS4, PS2; 13 points(VCEP specifications version 1; Approved: 1/31/2021) LINK:https://erepo.genome.network/evrepo/ui/classification/CA16602888/MONDO:0016054/018

• Frequency: Genomes: not found (cov: 32)
• Consequence: MTOR NM_004958.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:4
• 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]

MTOR (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PS2: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM5: For more information check the summary or visit ClinGen Evidence Repository.
• PP2: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MTOR	NM_004958.4	c.4448G>A	p.Cys1483Tyr	missense_variant	30/58	ENST00000361445.9	NP_004949.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MTOR	ENST00000361445.9	c.4448G>A	p.Cys1483Tyr	missense_variant	30/58	1	NM_004958.4	ENSP00000354558.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: reviewed by expert panel

Submissions by phenotype

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

Pathogenic, reviewed by expert panel

curation

ClinGen Brain Malformations Variant Curation Expert Panel

Feb 17, 2022

The c.4448G>A (NM_004958.4) variant in MTOR is a missense variant predicted to cause substitution of (p.Cys1483Tyr). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). MTOR, in which the variant was identified, is defined by the ClinGen 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 (PP2). A different amino acid change (p.Cys1483Arg), at this locus is classified as pathogenic for Overgrowth with or without cerebral malformations due to abnormalities in MTOR-pathway genes by the ClinGen BMEP (PM5). This variant resides within the kinase domain of MTOR that is defined as a critical functional domain by the ClinGen BMEP (PMIDs: 23322780, 27482884, 21210909) (PM1_Supporting). The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls (PS4; PMIDs: 22729223; 28892148; 25599672; 26619011; identified in 2 individuals with neuroimaging demonstrating at least one large cerebral hemisphere with cortical malformation(s), 1 individual with macrocephaly ( >=2 SD) and Developmental Delay or Intellectual disability without cortical malformations, it has been shown to demonstrate an increase cell growth phenotype in patient cell lines and at least 3 tumor samples in the literature and COSMIC). This variant has been confirmed de novo and has been identified with variable allelic fractions consistent with a post-zygotic event (PS2_Strong; PMID: 28892148). In summary, this variant meets the criteria to be classified as Pathogenic for mosaic autosomal dominant overgrowth with or without cerebral malformations due to abnormalities in MTOR-pathway genes based on the ACMG/AMP criteria applied, as specified by the ClinGen Brain Malformations Expert Panel: PM2_P, PP2, PM5, PM1_P, PS4, PS2; 13 points(VCEP specifications version 1; Approved: 1/31/2021) -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 19, 2022

For these reasons, this variant has been classified as Pathogenic. 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 expected to disrupt MTOR protein function. ClinVar contains an entry for this variant (Variation ID: 376453). This missense change has been observed in individual(s) with Smith-Kingsmore syndrome (PMID: 28892148). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 1483 of the MTOR protein (p.Cys1483Tyr). -

CEBALID syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

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, no assertion criteria provided

clinical testing

Undiagnosed Diseases Network, NIH

Jan 12, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	D
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.80	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Uncertain	0.27	D
MutationAssessor	Pathogenic	3.4	M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-9.6	D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.99	D
Vest4		0.94
MutPred		0.68		Loss of catalytic residue at L1484 (P = 0.0246);
MVP		0.95
MPC		2.4
ClinPred		1.0	D
GERP RS		5.3
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7
Varity_R		0.98
gMVP		0.97

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: rs786205165; hg19: chr1-11217230; COSMIC: COSV63869516; COSMIC: COSV63869516;