ClinVar Miner

Submissions for variant NM_000548.5(TSC2):c.5318A>G (p.His1773Arg) (rs45517418)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000234553 SCV000285456 uncertain significance Tuberous sclerosis 2 2015-11-26 criteria provided, single submitter clinical testing This sequence change replaces histidine with arginine at codon 1773 of the TSC2 protein (p.His1773Arg). The histidine residue is moderately conserved and there is a small physicochemical difference between histidine and arginine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. In summary, this is a novel missense change that is not predicted to affect protein function or cause disease. However the evidence is insufficient at this time to prove that conclusively. It has been classified as a Variant of Uncertain Significance.
GeneDx RCV000497390 SCV000590410 uncertain significance not provided 2017-06-12 criteria provided, single submitter clinical testing The H1773R variant in the TSC2 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The H1773R variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The H1773R variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In addition, this substitution occurs at a position that is not conserved, and in silico analysis predicts this variant likely does not alter the protein structure/function. A missense variant in the same residue (H1733P) has been reported previously in association with tuberous sclerosis complex, however, functional studies and prediction programs indicated that this variant was probably neutral (Hoogeveen-Westerveld et al., 2013). We interpret H1773R as a variant of uncertain significance.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000497390 SCV001248125 uncertain significance not provided 2019-07-01 criteria provided, single submitter clinical testing

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