Submissions for variant NM_000548.5(TSC2):c.1070C>T (p.Ala357Val)

gnomAD frequency: 0.00050  dbSNP: rs150195368

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000122202	SCV000205284	likely benign	not specified	2020-07-01	criteria provided, single submitter	clinical testing	The p.Ala357Val variant in TSC2 has been reported in 2 individuals with Tuberous Sclerosis-2 (Peron 2018 PMID: 29432982). It has also been identified in 0.092% (23/25098) (1 homozygote) Finnish chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID 41724). Functional studies indicate that this variant may not impact protein function (Hoogevenn-Westerveld 2011 PMID: 21309039). However, this in vitro assay may not accurately represent biological function. In addition, computational prediction tools and conservation analysis suggest that the Ala357Val variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, while the clinical significance of this variant is uncertain, its frequency suggests that it is more likely to be benign. ACMG/AMP Criteria applied: PS4_Moderate, BS1_Supporting.
Ambry Genetics	RCV000163628	SCV000214196	benign	Hereditary cancer-predisposing syndrome	2015-11-19	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000230505	SCV000285220	benign	Tuberous sclerosis 2	2025-01-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000034641	SCV000515014	benign	not provided	2020-06-09	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 21309039, 22703879, 23514105, 24728327, 22558107, 25801821, 24356096, 24631838, 22885699, 26580448, 29432982)
Eurofins Ntd Llc (ga)	RCV000122202	SCV000702129	likely benign	not specified	2016-10-31	criteria provided, single submitter	clinical testing
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000230505	SCV000845562	uncertain significance	Tuberous sclerosis 2	2018-08-07	criteria provided, single submitter	clinical testing
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000714826	SCV000845563	uncertain significance	Isolated focal cortical dysplasia type II	2018-08-07	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000034641	SCV001150684	likely benign	not provided	2024-12-01	criteria provided, single submitter	clinical testing	TSC2: BP4, BS2
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000034641	SCV002011359	likely benign	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000230505	SCV002041125	benign	Tuberous sclerosis 2	2021-11-07	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000163628	SCV002532742	likely benign	Hereditary cancer-predisposing syndrome	2021-08-02	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000230505	SCV004189644	benign	Tuberous sclerosis 2	2023-10-09	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. Homozygosity has been confirmed in one or more individuals. As homozygosity for pathogenic variants in this gene is generally assumed to result in embryonic lethality, this variant is unlikely to be pathogenic.
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034641	SCV000043524	variant of unknown significance	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Uncertain significance.
Tuberous sclerosis database (TSC2)	RCV000055595	SCV000083820	not provided	Tuberous sclerosis syndrome		no assertion provided	curation
ITMI	RCV000122202	SCV000086422	not provided	not specified	2013-09-19	no assertion provided	reference population
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000034641	SCV001800689	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000034641	SCV001921010	likely benign	not provided		no assertion criteria provided	clinical testing