ClinVar Miner

Submissions for variant NM_000548.5(TSC2):c.4635C>G (p.Ile1545Met)

dbSNP: rs757388437
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001040088 SCV001203643 uncertain significance Tuberous sclerosis 2 2024-01-10 criteria provided, single submitter clinical testing This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 1545 of the TSC2 protein (p.Ile1545Met). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TSC2-related conditions. ClinVar contains an entry for this variant (Variation ID: 838523). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt TSC2 protein function with a negative predictive value of 95%. 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.
GeneDx RCV001813810 SCV002061051 uncertain significance not provided 2022-01-17 criteria provided, single submitter clinical testing 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; Has not been previously published as pathogenic or benign to our knowledge
Ambry Genetics RCV002339198 SCV002635246 uncertain significance Hereditary cancer-predisposing syndrome 2022-10-11 criteria provided, single submitter clinical testing The p.I1545M variant (also known as c.4635C>G), located in coding exon 35 of the TSC2 gene, results from a C to G substitution at nucleotide position 4635. The isoleucine at codon 1545 is replaced by methionine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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