1-11128107-G-C

Variant names:

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

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM5 PS2_Moderate PM1_Supporting PS4_Moderate PS3_Supporting PP2 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.5930C>G (NM_004958.4) variant in MTOR is a missense variant predicted to cause substitution of (p.Thr1977Arg). 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.Thr1977Lys), 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). This variant has been shown to significantly increase phosphorylation levels in experiments with case and controls 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_M; PMIDs: 25799227, 29281825, identified in 2 individuals with neuropathology confirmatory of a malformation of cortical development, 1 individual with neuroimaging appearance consistent with a malformation of cortical development (without neuropathology), 5 tumor samples in the literature and COSMIC). 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, PM5, PM1_P, PS3_P, PS4_M, PS2_M; 10 points (VCEP specifications version 1; Approved: 1/31/2021) LINK:https://erepo.genome.network/evrepo/ui/classification/CA338394655/MONDO:0016054/018

• Frequency: Genomes: not found (cov: 33)
• Consequence: MTOR NM_004958.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P: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.
• 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 rank	MANE	Protein	UniProt
MTOR	NM_004958.4	c.5930C>G	p.Thr1977Arg	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>G	p.Thr1977Arg	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: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 17, 2022

ClinGen Brain Malformations Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.5930C>G (NM_004958.4) variant in MTOR is a missense variant predicted to cause substitution of (p.Thr1977Arg). 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.Thr1977Lys), 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). This variant has been shown to significantly increase phosphorylation levels in experiments with case and controls 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_M; PMIDs: 25799227, 29281825, identified in 2 individuals with neuropathology confirmatory of a malformation of cortical development, 1 individual with neuroimaging appearance consistent with a malformation of cortical development (without neuropathology), 5 tumor samples in the literature and COSMIC). 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, PM5, PM1_P, PS3_P, PS4_M, PS2_M; 10 points (VCEP specifications version 1; Approved: 1/31/2021) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.40
CADD	Uncertain	26
DANN	Uncertain	0.99
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	Uncertain	0.14	D
MetaRNN	Pathogenic	0.89	D;D
MetaSVM	Uncertain	0.59	D
MutationAssessor	Pathogenic	3.3	.;M
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-5.5	D;D
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0040	D;D
Polyphen		1.0	.;D
Vest4		0.92
MutPred		0.64		.;Gain of MoRF binding (P = 0.0056);
MVP		0.96
MPC		2.0
ClinPred		0.99	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.92
gMVP		0.96

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-11188164; COSMIC: COSV63869920; COSMIC: COSV63869920;