Submissions for variant NM_000548.5(TSC2):c.4070T>C (p.Ile1357Thr)

dbSNP: rs878854103

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000557479	SCV000644504	uncertain significance	Tuberous sclerosis 2	2025-01-23	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1357 of the TSC2 protein (p.Ile1357Thr). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TSC2-related conditions. ClinVar contains an entry for this variant (Variation ID: 468062). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt TSC2 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Sema4, Sema4	RCV002258957	SCV002533495	uncertain significance	Hereditary cancer-predisposing syndrome	2021-06-16	criteria provided, single submitter	curation
Ambry Genetics	RCV002258957	SCV002628187	uncertain significance	Hereditary cancer-predisposing syndrome	2024-06-28	criteria provided, single submitter	clinical testing	The p.I1357T variant (also known as c.4070T>C), located in coding exon 33 of the TSC2 gene, results from a T to C substitution at nucleotide position 4070. The isoleucine at codon 1357 is replaced by threonine, an amino acid with similar properties. This amino acid position is well conserved. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV003324763	SCV004030534	uncertain significance	not provided	2023-02-24	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Baylor Genetics	RCV003459241	SCV004206864	uncertain significance	Isolated focal cortical dysplasia type II	2023-08-20	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003999304	SCV004825808	uncertain significance	Tuberous sclerosis syndrome	2023-09-05	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with threonine at codon 1357 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 not been reported in individuals affected with TSC2-related disorders in the literature. This variant has not been identified 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.
Fulgent Genetics, Fulgent Genetics	RCV005018949	SCV005645099	uncertain significance	Lymphangiomyomatosis; Isolated focal cortical dysplasia type II; Tuberous sclerosis 2	2024-05-13	criteria provided, single submitter	clinical testing