ClinVar Miner

Submissions for variant NM_000548.5(TSC2):c.736A>G (p.Thr246Ala) (rs137854123)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000554931 SCV000644664 uncertain significance Tuberous sclerosis 2 2017-03-08 criteria provided, single submitter clinical testing This sequence change replaces threonine with alanine at codon 246 of the TSC2 protein (p.Thr246Ala). The threonine residue is highly conserved and there is a small physicochemical difference between threonine and alanine. This variant is present in population databases (rs137854123, ExAC 0.01%). This variant has been reported in the literature in two individuals affected with tuberous sclerosis complex from a single family, and in an unrelated individual with malignant melanoma (PMID: 18772611, 26994145). ClinVar contains an entry for this variant (Variation ID: 49384). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change with uncertain impact on protein function. It has been reported in both the population and affected individuals, but the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000612409 SCV000711361 uncertain significance not specified 2016-09-21 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The p.Thr246Ala variant in TSC2 has been reported in 1 Asian individual as well as one family m ember with Tuberous Sclerosis (Sasongko 2008). This variant has been identified in 1/10372 African chromosomes by the Exome Aggregation Consortium (ExAC, http:/ /exac.broadinstitute.org; dbSNP rs137854123). Computational prediction tools and conservation analysis suggest that the p.Thr246Ala variant may impact the prote in, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Thr246Ala variant is uncertain.
Tuberous sclerosis database (TSC2) RCV000042644 SCV000066439 not provided Tuberous sclerosis syndrome no assertion provided curation
CSER_CC_NCGL; University of Washington Medical Center RCV000042644 SCV000190674 uncertain significance Tuberous sclerosis syndrome 2014-06-01 no assertion criteria provided research

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