ClinVar Miner

Submissions for variant NM_000548.5(TSC2):c.2113G>A (p.Val705Met) (rs397515241)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000494277 SCV000583350 pathogenic not provided 2018-01-04 criteria provided, single submitter clinical testing The V705M pathogenic variant in the TSC2 gene has been reported previously in association withtuberous sclerosis complex (TSC) and has been shown to affect protein function (Hoogeveen-Westerveld et al., 2013). A different missense variant at the same position (V705E) has also been reported previously in association with TSC (Hoogeveen-Westerveld et al., 2013; van Eeghen et al., 2013). The V705M variant is not observed in large population cohorts (Lek et al., 2016). The V705M variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties; however, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Additionally, missense variants in nearby residues have been reported in the Human Gene Mutation Database in individuals with TSC (Stenson et al., 2014). Therefore, the presence of V705M is consistent with the diagnosis of TSC in this individual.
Center for Human Genetics, Inc RCV000660343 SCV000782401 pathogenic Tuberous sclerosis 2 2016-11-01 criteria provided, single submitter clinical testing
Invitae RCV000660343 SCV000953450 uncertain significance Tuberous sclerosis 2 2018-10-05 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 705 of the TSC2 protein (p.Val705Met). The valine residue is highly conserved and there is a small physicochemical difference between valine and methionine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual with suspected tuberous sclerosis complex (PMID: 22903760). ClinVar contains an entry for this variant (Variation ID: 65328). Experimental studies have shown that this missense change results in a protein that does not fully inhibit S6K phosphorylation, consistent with loss of function (PMID: 22903760). 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.
Tuberous sclerosis database (TSC2) RCV000055552 SCV000083776 not provided Tuberous sclerosis syndrome no assertion provided curation

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