Submissions for variant NM_000548.5(TSC2):c.3989C>T (p.Thr1330Met) (rs397515209)

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001703964	SCV000243697	likely benign	not provided	2021-04-07	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 22490766, 23514105)
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine	RCV000190025	SCV000540609	uncertain significance	not specified	2016-10-20	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Reported in 1 proband with features of TSC and the unaffected parent of a child with autism. ClinVar: VUS by GeneDx (who report they have seen it on their epilepsy panel?)
Invitae	RCV000458400	SCV000544529	benign	Tuberous sclerosis 2	2020-10-13	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000571810	SCV000664598	uncertain significance	Hereditary cancer-predisposing syndrome	2019-02-20	criteria provided, single submitter	clinical testing	The p.T1330M variant (also known as c.3989C>T), located in coding exon 32 of the TSC2 gene, results from a C to T substitution at nucleotide position 3989. The threonine at codon 1330 is replaced by methionine, an amino acid with similar properties. This alteration has been reported in a Korean patient with a definitive diagnosis of tuberous sclerosis complex (TSC) and in the mother of a proband with autism spectrum disorder (ASD), but not in the proband themself (Jang MA et al. Pediatr Neurol. 2012 Apr;46(4):222-4; Bahl S et al. Mol Autism. 2013 Mar 20;4(1):5). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Illumina Clinical Services Laboratory,Illumina	RCV000055604	SCV001274388	uncertain significance	Tuberous sclerosis syndrome	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Tuberous sclerosis database (TSC2)	RCV000055507	SCV000083730	not provided	Autism spectrum disorder		no assertion provided	curation
Tuberous sclerosis database (TSC2)	RCV000055604	SCV000083829	not provided	Tuberous sclerosis syndrome		no assertion provided	curation