Submissions for variant NM_000368.5(TSC1):c.346T>G (p.Leu116Val)

gnomAD frequency: 0.00029  dbSNP: rs199620268

Total submissions: 18

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	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.
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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001080106	SCV000284727	benign	Tuberous sclerosis 1	2024-01-30	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000725839	SCV000339865	uncertain significance	not provided	2016-03-08	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000372436	SCV000478259	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	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000122184	SCV000920328	likely benign	not specified	2023-01-12	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 0.00038 in 251236 control chromosomes (gnomAD). The observed variant frequency is approximately 15 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 the literature in an individual with, or suspected of 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 TSC1-TSC2, however TORC1 activity was estimated, not measured, and therefore this report is only indirect evidence for the benign nature of the variant. Eleven submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments, classifying the variant as either benign (n=4)/likely benign (n=5), or VUS (n=2). Based on the evidence outlined above, the variant was classified as likely benign.
CeGaT Center for Human Genetics Tuebingen	RCV000725839	SCV001155807	likely benign	not provided	2019-03-01	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000725839	SCV002009239	likely benign	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001080106	SCV002040172	benign	Tuberous sclerosis 1	2021-11-07	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000163292	SCV002531456	likely benign	Hereditary cancer-predisposing syndrome	2020-12-03	criteria provided, single submitter	curation
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000725839	SCV004221394	benign	not provided	2015-04-15	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000055005	SCV004840550	benign	Tuberous sclerosis syndrome	2024-02-05	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.
PreventionGenetics, part of Exact Sciences	RCV003934997	SCV004749598	likely benign	TSC1-related disorder	2019-06-30	no assertion criteria provided	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).