Submissions for variant NM_000548.5(TSC2):c.77C>T (p.Pro26Leu)

dbSNP: rs1555494636

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000520283	SCV000620582	uncertain significance	not provided	2017-09-08	criteria provided, single submitter	clinical testing	The P26L variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The P26L variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved in mammals, and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, missense variants in nearby residues have not been reported in the Human Gene Mutation Database in association with TSC (Stenson et al., 2014).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000556475	SCV000644670	uncertain significance	Tuberous sclerosis 2	2024-10-30	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 26 of the TSC2 protein (p.Pro26Leu). 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: 451829). 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.
Genome-Nilou Lab	RCV000556475	SCV002040522	uncertain significance	Tuberous sclerosis 2	2021-11-07	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004003631	SCV004829254	uncertain significance	Tuberous sclerosis syndrome	2023-09-17	criteria provided, single submitter	clinical testing	This missense variant replaces proline with leucine at codon 26 of the TSC2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, 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.
Ambry Genetics	RCV004678731	SCV005181184	uncertain significance	Hereditary cancer-predisposing syndrome	2024-05-02	criteria provided, single submitter	clinical testing	The p.P26L variant (also known as c.77C>T), located in coding exon 1 of the TSC2 gene, results from a C to T substitution at nucleotide position 77. The proline at codon 26 is replaced by leucine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.