ClinVar Miner

Submissions for variant NM_000368.4(TSC1):c.1139C>G (p.Thr380Ser) (rs1064796512)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000478581 SCV000573307 uncertain significance not provided 2017-02-10 criteria provided, single submitter clinical testing The T380S variant has notbeen published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge.The T380S variant is not observed in large population cohorts (Lek et al., 2016; 1000 GenomesConsortium et al., 2015; Exome Variant Server). The T380S variant is a conservative amino acidsubstitution, which is not likely to impact secondary protein structure as these residues share similarproperties. This substitution occurs at a position that is not conserved. In silico analysis is inconsistentin its predictions as to whether or not the variant is damaging to the protein structure/function.Additionally, the vast majority of TSC1 pathogenic variants result in protein truncation, whilemissense variants have been reported only rarely (Northrup et al., 2011; Au et al., 2007).
Invitae RCV000684873 SCV000812334 uncertain significance Tuberous sclerosis 1 2018-04-16 criteria provided, single submitter clinical testing This sequence change replaces threonine with serine at codon 380 of the TSC1 protein (p.Thr380Ser). The threonine residue is weakly conserved and there is a small physicochemical difference between threonine and serine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with TSC1-related disease. ClinVar contains an entry for this variant (Variation ID: 423590). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.

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