ClinVar Miner

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

gnomAD frequency: 0.00022  dbSNP: rs118203504
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Total submissions: 18
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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 Co-occurence with a mutation in another gene that clearly explains a proband's phenotype;In silico models in agreement (benign);Other data supporting benign classification;Subpopulation frequency in support of benign classification
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)
Invitae RCV001082139 SCV000284669 benign Tuberous sclerosis 1 2021-12-17 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics 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 2022-06-01 criteria provided, single submitter clinical testing
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

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