1-11128107-G-T

Variant names:

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

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1_Supporting PS4 PS2_Moderate PS3_Supporting PP2 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.5930C>A (NM_004958.4) variant in MTOR is a missense variant predicted to cause substitution of (p.Thr1977Lys). 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). 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). This variant has been shown to significantly increase phosphorylation levels in experiments with case and control cells of similar isogenic backgrounds indicating that this variant impacts protein function (PMID:24631838) (PS3_Supporting). The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls (PS4; PMIDs w/ phenotypes). Testing of unaffected and affected tissue show variable allelic fractions consistent with a post-zygotic event (PS2_Moderate; PMID:25799227). 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, PM1_P, PS3_P, PS4, PS2_M; 10 points (VCEP specifications version 1; Approved: 1/31/2021) LINK:https://erepo.genome.network/evrepo/ui/classification/CA248390/MONDO:0016054/018

• Frequency: Genomes: not found (cov: 33)
• Consequence: MTOR NM_004958.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:3 O:1
• 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 10 ACMG points.

• PS2: For more information check the summary or visit ClinGen Evidence Repository.
• PS3: 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.
• PP2: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTOR	NM_004958.4	c.5930C>A	p.Thr1977Lys	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>A	p.Thr1977Lys	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:3 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

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

Feb 12, 2022

ClinGen Brain Malformations Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.5930C>A (NM_004958.4) variant in MTOR is a missense variant predicted to cause substitution of (p.Thr1977Lys). 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). 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). This variant has been shown to significantly increase phosphorylation levels in experiments with case and control cells of similar isogenic backgrounds indicating that this variant impacts protein function (PMID: 24631838) (PS3_Supporting). The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls (PS4; PMIDs w/ phenotypes). Testing of unaffected and affected tissue show variable allelic fractions consistent with a post-zygotic event (PS2_Moderate; PMID: 25799227). 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, PM1_P, PS3_P, PS4, PS2_M; 10 points (VCEP specifications version 1; Approved: 1/31/2021) -

Isolated focal cortical dysplasia type II Pathogenic:1

Dec 17, 2024

Clinical Genomics Laboratory, Washington University in St. Louis

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

An MTOR c.5930C>A (p.Thr1977Lys) variant was identified at an allelic fraction consistent with somatic origin. This variant has been identified in numerous individuals with focal cortical dysplasia (Baldassari S et al., PMID: 31444548; Lim JS et al., PMID: 25799227; D'Gama AM et al., PMID: 29281825; Lim JS et al., PMID: 25799227). It has also been reported as a somatic variant in various types of malignancies in the cancer database COSMIC (Genomic mutation ID: COSV63869673). The MTOR c.5930C>A (p.Thr1977Lys) variant has been reported in the ClinVar database as a germline pathogenic variant by two submitters, including an expert panel (ClinVar ID: 156702). It is absent from the general population database (gnomAD v4.1.0), indicating it is not a common variant. This 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; Murugan AK et al., PMID: 23322780; Hardt M et al., PMID: 21210909). Other variants in the same codon, (p.Thr1977Ile and p.Thr1977Arg), have been reported in individuals with brain malformations and are considered pathogenic (Handoko, M et al. PMID: 30569621; Mirzaa GM et al., PMID: 27159400; Cao Y et al. PMID: 31349857; D'Gama AM et al., PMID: 29281825; ClinVar ID's: 1296989 and 584432). Computational predictors indicate that the variant is damaging, evidence that correlates with impact to MTOR function. In support of this prediction, functional studies led to increased S6K1 phosphorylation, evidence that correlates with an impact on MTOR function (Grabiner BC et al., PMID: 24631838). 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.5930C>A (p.Thr1977Lys) variant is classified as pathogenic. -

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

Feb 02, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0101 - Gain-of-function is a known mechanism of disease for this gene. (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from threonine to lysine (exon 43). (N) 0251 - Variant is heterozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0502 - Missense variant with conflicting in silico predictions and/or uninformative conservation. (N) 0600 - Variant is located in an annotated domain or motif. (FAT domain; NCBI) (N) 0702 - Comparable variants have strong previous evidence for pathogenicity. (p.(Thr1977Ile) in patients with focal cortical dysplasia; ClinVar, PMID: 27159400). (P) 0802 - Moderate previous evidence of pathogenicity in unrelated individuals. (In 4 patients with focal cortical dysplasia; PMID: 25799227, 29281825, 31444548) (P) 0905 - No segregation evidence has been identified for this variant. (N) 1002 - Moderate functional evidence supporting abnormal protein function. Gain-of-function was demonstrated in animal models. (PMID: 27482884) (P) 1204 - Variant shown to be de novo in proband (parental status not tested but assumed). (P) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -

not provided Other:1

-

James Howe Lab, University of Iowa Hospital and Clinics

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.40	T;D
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.89	D;D
MetaSVM	Uncertain	0.58	D
MutationAssessor	Pathogenic	3.3	.;M
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-5.5	D;D
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0050	D;D
Polyphen		1.0	.;D
Vest4		0.92
MutPred		0.66		.;Gain of MoRF binding (P = 0.0207);
MVP		0.97
MPC		2.1
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.91
gMVP		0.94

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: COSV63869673; COSMIC: COSV63869673;