ClinVar Miner

Submissions for variant NM_000548.5(TSC2):c.3212C>T (p.Thr1071Ile) (rs45498892)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000574600 SCV000664679 uncertain significance Hereditary cancer-predisposing syndrome 2016-08-24 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000513743 SCV000610258 uncertain significance not provided 2017-08-24 criteria provided, single submitter clinical testing
Invitae RCV000465303 SCV000544490 uncertain significance Tuberous sclerosis 2 2016-08-20 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 1071 of the TSC2 protein (p.Thr1071Ile). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a TSC2-related disease. 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: "Probably Damaging"; Align-GVGD: "Class C0"). A different missense substitution at this codon (p.Thr1071Arg) has been determined to be likely pathogenic (PMID: 1112665). This suggests that the threonine residue is critical for TSC2 protein function and that other missense substitution at this position may also be deleterious for protein function. In summary, this variant is a novel missense change with uncertain impact on protein function. Although a different substitution at this same codon has been determined to be likely pathogenic, further evidence is needed to conclusively classify this variant. Therefore, it has been classified as a Variant of Uncertain Significance.

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