Submissions for variant NM_000368.5(TSC1):c.1208C>T (p.Ser403Leu)

gnomAD frequency: 0.00036  dbSNP: rs118203504

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000163452	SCV000213999	benign	Hereditary cancer-predisposing syndrome	2016-09-27	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.
GeneDx	RCV000514892	SCV000243460	benign	not provided	2020-07-28	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 23514105, 28873162, 27930734, 24728327, 31623367)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001082139	SCV000284669	benign	Tuberous sclerosis 1	2025-02-04	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000122186	SCV000303842	likely benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000383299	SCV000478239	benign	Isolated focal cortical dysplasia type II	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Illumina Laboratory Services, Illumina	RCV001082139	SCV000478240	likely benign	Tuberous sclerosis 1	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000514892	SCV000609928	likely benign	not provided	2017-08-23	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000514892	SCV001155799	likely benign	not provided	2024-07-01	criteria provided, single submitter	clinical testing	TSC1: BS1
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000122186	SCV001983457	benign	not specified	2021-09-27	criteria provided, single submitter	clinical testing	Variant summary: TSC1 c.1208C>T (p.Ser403Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00035 in 251090 control chromosomes, predominantly at a frequency of 0.00061 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 24 fold of the estimated maximal expected allele frequency for a pathogenic variant in TSC1 causing Tuberous Sclerosis Complex phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no occurrence of c.1208C>T in individuals affected with Tuberous Sclerosis Complex and no experimental evidence demonstrating its impact on protein function have been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (benign/likely benign n=6, VUS n=1). Based on the evidence outlined above, the variant was classified as benign.
Genome-Nilou Lab	RCV001082139	SCV002040120	benign	Tuberous sclerosis 1	2021-11-07	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000122186	SCV002072263	likely benign	not specified	2021-10-19	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000163452	SCV002530883	benign	Hereditary cancer-predisposing syndrome	2021-04-05	criteria provided, single submitter	curation
Tuberous sclerosis database (TSC1)	RCV000041998	SCV000065778	not provided	Tuberous sclerosis syndrome		no assertion provided	curation
ITMI	RCV000122186	SCV000086403	not provided	not specified	2013-09-19	no assertion provided	reference population
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000514892	SCV001740748	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000514892	SCV001809198	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000514892	SCV001922511	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000122186	SCV001968713	benign	not specified		no assertion criteria provided	clinical testing