ClinVar Miner

Submissions for variant NM_000368.4(TSC1):c.3086G>T (p.Ser1029Ile) (rs796053450)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000189858 SCV000243511 uncertain significance not provided 2014-11-20 criteria provided, single submitter clinical testing p.Ser1029Ile (AGT>ATT): c.3086 G>T in exon 23 of the TSC1 gene (NM_000368.4). The S1029I variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The S1029I variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution occurs at a position that is not conserved across species, and in silico analysis predicts this variant likely does not alter the protein structure/function. Additionally, the vast majority of TSC1 mutations result in protein truncation, while missense mutations have been reported only rarely (Northrup et al., 2011; Au et al., 2007). Therefore, based on the currently available information, it is unclear whether S1029I is a pathogenic mutation or a rare benign variant. The variant is found in TUBSC-EPIV2,TSC1 panel(s).
Invitae RCV000557141 SCV000641622 uncertain significance Tuberous sclerosis 1 2017-06-16 criteria provided, single submitter clinical testing This sequence change replaces serine with isoleucine at codon 1029 of the TSC1 protein (p.Ser1029Ile). The serine residue is moderately conserved and there is a large physicochemical difference between serine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with a TSC1-related disease. ClinVar contains an entry for this variant (Variation ID: 207639). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, this variant has uncertain impact on TSC1 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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