ClinVar Miner

Submissions for variant NM_000548.5(TSC2):c.5221A>G (p.Ile1741Val)

gnomAD frequency: 0.00001  dbSNP: rs140526185
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000469868 SCV000544505 uncertain significance Tuberous sclerosis 2 2023-12-31 criteria provided, single submitter clinical testing This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1741 of the TSC2 protein (p.Ile1741Val). 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: 406082). 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 RCV000497871 SCV000590651 uncertain significance not provided 2021-11-29 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Genome-Nilou Lab RCV000469868 SCV002040887 uncertain significance Tuberous sclerosis 2 2021-11-07 criteria provided, single submitter clinical testing
Ambry Genetics RCV002348294 SCV002646732 uncertain significance Hereditary cancer-predisposing syndrome 2020-11-03 criteria provided, single submitter clinical testing The p.I1741V variant (also known as c.5221A>G), located in coding exon 40 of the TSC2 gene, results from an A to G substitution at nucleotide position 5221. The isoleucine at codon 1741 is replaced by valine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Baylor Genetics RCV003463866 SCV004205062 uncertain significance Isolated focal cortical dysplasia type II 2023-06-15 criteria provided, single submitter clinical testing

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