Submissions for variant NM_000548.5(TSC2):c.4105C>T (p.Arg1369Trp)

gnomAD frequency: 0.00026  dbSNP: rs45517328

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000726579	SCV000243703	benign	not provided	2018-04-02	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 27601542, 26703369, 23514105, 25925381, 21309039)
Eurofins Ntd Llc (ga)	RCV000726579	SCV000345655	uncertain significance	not provided	2018-06-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000042816	SCV000395645	likely benign	Tuberous sclerosis syndrome	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.
Invitae	RCV001082851	SCV000544473	benign	Tuberous sclerosis 2	2024-01-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000565844	SCV000675488	likely benign	Hereditary cancer-predisposing syndrome	2019-02-08	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
CeGaT Center for Human Genetics Tuebingen	RCV000726579	SCV001150717	likely benign	not provided	2024-01-01	criteria provided, single submitter	clinical testing	TSC2: BS2
Genome-Nilou Lab	RCV001082851	SCV002039828	benign	Tuberous sclerosis 2	2021-11-07	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000565844	SCV002533502	benign	Hereditary cancer-predisposing syndrome	2021-05-03	criteria provided, single submitter	curation
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000726579	SCV004221454	benign	not provided	2018-12-17	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003488361	SCV004241253	likely benign	not specified	2023-12-18	criteria provided, single submitter	clinical testing	Variant summary: TSC2 c.4105C>T (p.Arg1369Trp) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00024 in 248644 control chromosomes (gnomAD). The observed variant frequency is approximately 3.45 fold of the estimated maximal expected allele frequency for a pathogenic variant in TSC2 causing Tuberous Sclerosis Complex phenotype (6.9e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.4105C>T in individuals affected with Tuberous Sclerosis Complex has been reported. At least one publication reports experimental evidence evaluating an impact on protein function (Hoogeveen-Westerveld_2011). These results showed no damaging effect of this variant. The following publication has been ascertained in the context of this evaluation (PMID: 21309039). Ten submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as benign (n=4), likely benign (n=5), or uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as likely benign.
Color Diagnostics, LLC DBA Color Health	RCV001082851	SCV004360915	benign	Tuberous sclerosis 2	2022-08-31	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000726579	SCV004564718	likely benign	not provided	2023-06-28	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003952467	SCV004768389	likely benign	TSC2-related condition	2022-02-17	criteria provided, single submitter	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).
Tuberous sclerosis database (TSC2)	RCV000042816	SCV000066612	not provided	Tuberous sclerosis syndrome		no assertion provided	curation
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000726579	SCV001809636	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000726579	SCV001926167	likely benign	not provided		no assertion criteria provided	clinical testing