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

gnomAD frequency: 0.00002  dbSNP: rs397515209

Total submissions: 12

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, Mass General Brigham 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?)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000458400	SCV000544529	benign	Tuberous sclerosis 2	2025-01-12	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000571810	SCV000664598	likely benign	Hereditary cancer-predisposing syndrome	2021-04-01	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.
Illumina Laboratory Services, 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.
Genome-Nilou Lab	RCV000458400	SCV002039804	likely benign	Tuberous sclerosis 2	2021-11-07	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000055604	SCV004817488	uncertain significance	Tuberous sclerosis syndrome	2024-01-05	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with methionine at codon 1330 of the TSC2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with tuberous sclerosis complex (TSC; PMID: 22490766) but also in an unaffected individual (PMID: 23514105) . This variant has been identified in 10/276322 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Myriad Genetics, Inc.	RCV000458400	SCV005405991	likely benign	Tuberous sclerosis 2	2024-08-06	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001703964	SCV005622711	uncertain significance	not provided	2024-11-08	criteria provided, single submitter	clinical testing	The TSC2 c.3989C>T (p.Thr1330Met) variant has been reported in the published literature in in an individual affected with tuberous sclerosis complex (PMID: 22490766 (2012)), as well as in a reportedly healthy individual (PMID: 23514105 (2013)). The frequency of this variant in the general population, 0.0002 (4/19734 chromosomes in East Asian subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant.
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
PreventionGenetics, part of Exact Sciences	RCV004542721	SCV004760105	likely benign	TSC2-related disorder	2023-08-03	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).