Submissions for variant NM_000548.5(TSC2):c.5116C>T (p.Arg1706Cys)

gnomAD frequency: 0.00029  dbSNP: rs45517391

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000189943	SCV000243610	benign	not specified	2016-06-08	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	RCV001082733	SCV000285440	benign	Tuberous sclerosis 2	2024-02-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000043179	SCV000395675	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.
CeGaT Center for Human Genetics Tuebingen	RCV000512881	SCV000608741	likely benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing	TSC2: BS1
Ambry Genetics	RCV000571102	SCV000675489	likely benign	Hereditary cancer-predisposing syndrome	2019-02-11	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000189943	SCV000918329	likely benign	not specified	2018-03-17	criteria provided, single submitter	clinical testing	Variant summary: TSC2 c.5116C>T (p.Arg1706Cys) results in a non-conservative amino acid change located in the Rap GTPase activating protein domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The observed variant frequency is approximately 4-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. The variant, c.5116C>T, has been reported in the literature in individuals affected with Tuberous Sclerosis Complex (Jozwiak_2014). These report(s) do not provide unequivocal conclusions about association of the variant with Tuberous Sclerosis Complex. A functional study, Hoogeveen-Westerveld_2012, found the variant to act comparable to wild type protein and classified as probably neutral. An internal specimen reports the variant to co-occur with pathogenic FLCN, c.927_954dup28. Multiple ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as "likely benign/benign." Based on the evidence outlined above, the variant was classified as likely benign.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000512881	SCV002011325	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001082733	SCV002040251	benign	Tuberous sclerosis 2	2021-11-07	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University Hospital Muenster	RCV002222154	SCV002499719	uncertain significance	See cases	2022-03-17	criteria provided, single submitter	clinical testing	ACMG categories: BP1
Sema4, Sema4	RCV000571102	SCV002534016	benign	Hereditary cancer-predisposing syndrome	2020-10-19	criteria provided, single submitter	curation
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000189943	SCV002774082	benign	not specified	2021-07-20	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001082733	SCV004236975	uncertain significance	Tuberous sclerosis 2	2023-06-09	criteria provided, single submitter	clinical testing
Tuberous sclerosis database (TSC2)	RCV000043179	SCV000066979	not provided	Tuberous sclerosis syndrome		no assertion provided	curation
Genetic Services Laboratory, University of Chicago	RCV000189943	SCV003839174	likely benign	not specified	2022-11-29	no assertion criteria provided	clinical testing