Submissions for variant NM_004958.4(MTOR):c.5501C>T (p.Thr1834Met)

gnomAD frequency: 0.00036  dbSNP: rs142403193

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Brain Malformations Variant Curation Expert Panel	RCV001836914	SCV001949952	likely benign	Overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes	2022-02-12	reviewed by expert panel	curation	The c.5501C>T (NM_004958.4) variant in MTOR is a missense variant predicted to cause substitution of (p.Thr1834Met). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0006661 in European (non Finnish) population, which is higher than the ClinGen BMEP threshold ([>0.00037]) for BS1, and therefore meets this criterion (BS1). 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 focal adhesion kinase domain of MTOR that is defined as a critical functional domain by the ClinGen BMEP (PMIDs: 23322780, 27482884, 21210909) (PM1_Supporting). In summary, this variant meets the criteria to be classified as Likely benign 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: BS1, PP2, PM1_P; -2 points (VCEP specifications version 1; Approved: 1/31/2021)
Invitae	RCV000861765	SCV001002162	benign	not provided	2024-01-30	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000861765	SCV001501876	likely benign	not provided	2024-04-01	criteria provided, single submitter	clinical testing	MTOR: BP4, BS2
GeneDx	RCV000861765	SCV001846022	benign	not provided	2019-07-10	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001816928	SCV002066998	likely benign	not specified	2019-12-02	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002536229	SCV003537186	likely benign	Inborn genetic diseases	2021-07-19	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
PreventionGenetics, part of Exact Sciences	RCV003928337	SCV004740933	likely benign	MTOR-related disorder	2022-05-10	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).