ClinVar Miner

Submissions for variant NM_000368.4(TSC1):c.346T>G (p.Leu116Val) (rs199620268)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000163292 SCV000213820 likely benign Hereditary cancer-predisposing syndrome 2019-03-28 criteria provided, single submitter clinical testing Intact protein function observed in appropriate functional assay(s);Other data supporting benign classification;Structural Evidence
GeneDx RCV000122184 SCV000243454 benign not specified 2016-09-21 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae RCV001080106 SCV000284727 benign Tuberous sclerosis 1 2019-12-31 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000725839 SCV000339865 uncertain significance not provided 2016-03-08 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000372436 SCV000478259 benign 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 Clinical Services Laboratory,Illumina RCV001080106 SCV000478260 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.
Integrated Genetics/Laboratory Corporation of America RCV000122184 SCV000920328 likely benign not specified 2018-02-02 criteria provided, single submitter clinical testing Variant summary: TSC1 c.346T>G (p.Leu116Val) results in a 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 0.00037 in 276968 control chromosomes. The observed variant frequency is approximately 14.88 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 benign. c.346T>G has been reported in one individual with, or suspected as having, Tuberous Sclerosis Complex, without strong evidence for causality (Hoogeveen-Westerveld_2011). This same report included an in vitro study which showed the variant did not have a significantly higher T389/S6K ratio than wild-type TSC1TSC2, however TORC1 activity was estimated, not measured, therefore this report is indirect evidence for the benign nature of the variant. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, with conflicting classifications (VUS, likely benign, benign). Based on the evidence outlined above, the variant was classified as likely benign.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000725839 SCV001155807 uncertain significance not provided 2019-10-01 criteria provided, single submitter clinical testing
Tuberous sclerosis database (TSC1) RCV000055005 SCV000083223 not provided Tuberous sclerosis syndrome no assertion provided curation
Tuberous sclerosis database (TSC1) RCV000055027 SCV000083245 not provided Autism spectrum disorder no assertion provided curation
ITMI RCV000122184 SCV000086401 not provided not specified 2013-09-19 no assertion provided reference population
CSER _CC_NCGL, University of Washington RCV000055005 SCV000503541 uncertain significance Tuberous sclerosis syndrome 2016-08-01 no assertion criteria provided research Found in patient having exome sequencing for an unrelated indication. No known history of Tuberous sclerosis complex.

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