Submissions for variant NM_000548.5(TSC2):c.1477C>T (p.Leu493Phe)

dbSNP: rs45517177

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000189981	SCV000243652	uncertain significance	not provided	2013-11-27	criteria provided, single submitter	clinical testing	p.Leu493Phe (CTC>TTC): c.1477 C>T in exon 15 of the TSC2 gene (NM_000548.3)The Leu493Phe missense change has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This variant is a conservative substitution, as Leucine and Phenylalanine are both uncharged, non-polar amino acids. However, it alters a position that is highlyconserved across species. Additionally, other amino acid substitutions at the same position (Leu493Pro and Leu493Val) have been reported in patients with clinical features of tuberous sclerosis, and these variants were considered to be probably pathogenic based on the results of in vitro functional studies (TSC2 LOVD; Hoogeveen-Westerveld et al., 2013). In silico analysis is inconsistent with regard to the effect the Leu493Phe variant may have on the protein structure/function. Therefore, based on the currently available information, it is unclear whether Leu493Phe is a disease-causing mutation or a rare benign variant. The variant is found in EPILEPSY panel(s).
Invitae	RCV001857664	SCV002309755	uncertain significance	Tuberous sclerosis 2	2022-09-01	criteria provided, single submitter	clinical testing	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. This variant disrupts the p.Leu493 amino acid residue in TSC2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12111193, 22903760, 29500070; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt TSC2 protein function. ClinVar contains an entry for this variant (Variation ID: 207716). This variant has not been reported in the literature in individuals affected with TSC2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 493 of the TSC2 protein (p.Leu493Phe).