ClinVar Miner

Submissions for variant NM_000368.4(TSC1):c.1063A>G (p.Met355Val) (rs1302832406)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000521961 SCV000616963 uncertain significance not specified 2017-09-21 criteria provided, single submitter clinical testing The M355V variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The M355V variant is not observed in large population cohorts (Lek et al., 2016). This variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to Methionine are tolerated across species. The vast majority of TSC1 pathogenic variants result in protein truncation, while missense variants have been reported only rarely (Northrup et al., 2011; Au et al., 2007). In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.
Invitae RCV000795024 SCV000934462 uncertain significance Tuberous sclerosis 1 2019-12-12 criteria provided, single submitter clinical testing This sequence change replaces methionine with valine at codon 355 of the TSC1 protein (p.Met355Val). The methionine residue is moderately conserved and there is a small physicochemical difference between methionine and valine. 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: 449149). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine 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.
Ambry Genetics RCV001009796 SCV001169909 uncertain significance Hereditary cancer-predisposing syndrome 2019-04-15 criteria provided, single submitter clinical testing Insufficient evidence

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