ClinVar Miner

Submissions for variant NM_000548.5(TSC2):c.5126C>T (p.Pro1709Leu)

dbSNP: rs45517393
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000693889 SCV000822311 pathogenic Tuberous sclerosis 2 2025-01-22 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 1709 of the TSC2 protein (p.Pro1709Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with tuberous sclerosis complex (PMID: 8824881, 10732801, 11112665, 11520734, 22867869, 22903760). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 49929). 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%. Experimental studies have shown that this missense change affects TSC2 function (PMID: 22903760). For these reasons, this variant has been classified as Pathogenic.
Division of Genomic Medicine, Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University RCV000693889 SCV002559807 pathogenic Tuberous sclerosis 2 2022-07-19 criteria provided, single submitter clinical testing According to ACMG GL 2015, this variant was detected de novo as a mosaic mutation (PS2), located in the GAP domain (PM1), absent from controls (PM2). Multiple lines of computational evidence support a deleterious effect (PP3), and reported as pathogenic in LOVD database (PP5).
GeneDx RCV004700315 SCV005201654 pathogenic not provided 2023-04-24 criteria provided, single submitter clinical testing Published functional studies demonstrate less effective inhibition of TORC1 activity (Hoogeveen-Westerveld et al., 2013); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28968464, 30036593, 35571021, 18466115, 10732801, 11520734, 15798777, 22867869, 8824881, 32211034, 11112665, 22903760)
Tuberous sclerosis database (TSC2) RCV000043196 SCV000066997 not provided Tuberous sclerosis syndrome no assertion provided curation

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