ClinVar Miner

Submissions for variant NM_000548.5(TSC2):c.1982_1983delinsTT (p.Gly661Val)

dbSNP: rs137854103
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000571827 SCV000675780 uncertain significance Hereditary cancer-predisposing syndrome 2022-03-23 criteria provided, single submitter clinical testing The c.1982_1983delGCinsTT variant (also known as p.G661V), located in coding exon 18 of the TSC2 gene, results from an in-frame deletion of GC and insertion of TT at nucleotide positions 1982 to 1983. This results in the substitution of the glycine residue for a valine residue at codon 661, an amino acid with dissimilar properties. In one functional study, this alteration was found to have similar TSC1-TSC2 dependent inhibition of TORC1 as wild-type (Hoogeveen-Westerveld M et al. Hum. Mutat., 2013 Jan;34:167-75). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be inconclusive by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV001209976 SCV001381439 uncertain significance Tuberous sclerosis 2 2024-01-02 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 661 of the TSC2 protein (p.Gly661Val). Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This missense change has been observed in individual(s) with clinical features of tuberous sclerosis complex (PMID: 22903760). ClinVar contains an entry for this variant (Variation ID: 49698). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Experimental studies have shown that this missense change does not substantially affect TSC2 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.
GeneDx RCV001753455 SCV001997143 uncertain significance not provided 2019-12-13 criteria provided, single submitter clinical testing Not observed in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Published functional studies demonstrate no damaging effect: immunoblot expression assay comparable to wild type (Hoogeveen-Westerveld 2013); This variant is associated with the following publications: (PMID: 22903760)
Genome-Nilou Lab RCV001209976 SCV002040658 uncertain significance Tuberous sclerosis 2 2021-11-07 criteria provided, single submitter clinical testing
Tuberous sclerosis database (TSC2) RCV000042961 SCV000066758 not provided Tuberous sclerosis syndrome no assertion provided curation

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