Submissions for variant NM_004958.4(MTOR):c.5395G>A (p.Glu1799Lys)

dbSNP: rs863225264

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000255268	SCV000321909	pathogenic	not provided	2021-12-30	criteria provided, single submitter	clinical testing	Functional studies indicate that E1799K results in an increase in mTOR pathway activity, suggesting a gain-of-function mechanism of disease (Baynam, et al., 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27739187, 27159400, 25851998, 26542245, 27513193, 27753196, 28892148, 28475857, 32581362, 33077954, 23636326, 24631838, 31441589, 31064327, 30764584, 30050716, 29296277, 27860216, 28007777, 24625776, 26432419)
Ambry Genetics	RCV000624365	SCV000741517	pathogenic	Inborn genetic diseases	2016-04-27	criteria provided, single submitter	clinical testing
Invitae	RCV000255268	SCV000965481	pathogenic	not provided	2023-12-13	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1799 of the MTOR protein (p.Glu1799Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Smith–Kingsmore syndrome or MTOR-related megalencephaly and intellectual disability (PMID: 25851998, 26542245, 27159400, 27513193, 27753196, 28475857). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 217823). 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 with a negative predictive value of 95%. Experimental studies have shown that this missense change affects MTOR function (PMID: 24631838, 25851998). For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000255268	SCV001247275	pathogenic	not provided	2019-11-01	criteria provided, single submitter	clinical testing
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV001260508	SCV001437529	pathogenic	CEBALID syndrome	2020-09-01	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000201885	SCV001439961	pathogenic	Macrocephaly-intellectual disability-neurodevelopmental disorder-small thorax syndrome	2019-01-01	criteria provided, single submitter	clinical testing	This variant was identified as de novo.
Baylor Genetics	RCV001329983	SCV001521562	pathogenic	Isolated focal cortical dysplasia type II	2019-07-10	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Génétique des Maladies du Développement, Hospices Civils de Lyon	RCV001544505	SCV001762520	pathogenic	Intellectual disability	2021-08-02	criteria provided, single submitter	clinical testing	de novo variant, absent from gnomAD. Smith-Kingsmore syndrome
Illumina Laboratory Services, Illumina	RCV000201885	SCV001786563	pathogenic	Macrocephaly-intellectual disability-neurodevelopmental disorder-small thorax syndrome	2021-03-22	criteria provided, single submitter	clinical testing	The MTOR c.5395G>A (p.Glu1799Lys) variant is a missense variant that has been described in a heterozygous state in at least 12 individuals from seven unrelated families with features of Smith-Kingsmore syndrome (Baynam et al. 2015; Mroske et al. 2015; Mirzaa et al. 2016; Moosa et al. 2017; Gordo et al. 2018; Dobyns and Mirzaa 2019). An additional feature of multiple intestinal polyps was reported in one individual. In multiple cases, the variant was shown to occur de novo. In at least three families, the variant was found in multiple affected children despite not being detected in the parent's blood, suggesting gonadal mosaicism. The p.Glu1799Lys variant is not reported in the Genome Aggregation Database in a region of good sequence coverage, so the variant is presumed to be rare. Glu1799 is located in the FAT domain, which serves to regulate MTOR activity, and experiments in patient cells, human cell lines, and cultured rodent neurons have confirmed a gain-of-function effect of the p.Glu1799Lys variant (Grabiner et al. 2014; Baynam et al. 2015; Mirzaa et al. 2016). Based on the collective evidence, the p.Glu1799Lys variant is classified as pathogenic for Smith-Kingsmore syndrome.
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000255268	SCV002051550	pathogenic	not provided	2020-12-30	criteria provided, single submitter	clinical testing	PS4, PS3, PM6
Centogene AG - the Rare Disease Company	RCV000201885	SCV002059570	pathogenic	Macrocephaly-intellectual disability-neurodevelopmental disorder-small thorax syndrome	2021-06-21	criteria provided, single submitter	clinical testing
Eurofins-Biomnis	RCV000201885	SCV003935104	pathogenic	Macrocephaly-intellectual disability-neurodevelopmental disorder-small thorax syndrome	2022-09-30	criteria provided, single submitter	clinical testing
Molecular Genetics Lab, CHRU Brest	RCV003883143	SCV004697599	pathogenic	Isolated focal cortical dysplasia type II; Macrocephaly-intellectual disability-neurodevelopmental disorder-small thorax syndrome		criteria provided, single submitter	clinical testing
OMIM	RCV000201885	SCV000256631	pathogenic	Macrocephaly-intellectual disability-neurodevelopmental disorder-small thorax syndrome	2015-07-01	no assertion criteria provided	literature only
NIHR Bioresource Rare Diseases, University of Cambridge	RCV001003568	SCV001161929	pathogenic	Intellectual disability, severe		no assertion criteria provided	research
Service de Génétique Moléculaire, Hôpital Robert Debré	RCV001256976	SCV001433522	pathogenic	Rare genetic intellectual disability		no assertion criteria provided	clinical testing
Yale Center for Mendelian Genomics, Yale University	RCV000201885	SCV002106928	pathogenic	Macrocephaly-intellectual disability-neurodevelopmental disorder-small thorax syndrome	2020-10-19	no assertion criteria provided	literature only