ClinVar Miner

Submissions for variant NM_000368.4(TSC1):c.898A>G (p.Thr300Ala) (rs796053456)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000189843 SCV000243496 uncertain significance not provided 2012-10-17 criteria provided, single submitter clinical testing p.Thr300Ala (ACA>GCA):c.898 A>G in exon 9 of the TSC1 gene (NM_000368.3). The Thr300Ala missense change has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The NHLBI ESP Exome Variant Project has not identified Thr300Ala in approximately 6,500 individuals of European or African American ethnicity, indicating that it is not a common benign variant in these populations. The amino acid substitution is non-conservative, as a polar Threonine residue is replaced by a non-polar Alanine residue. However, Thr300Ala alters a position in the hamartin protein that is not highly conserved and several in silico algorithms predict that it is benign. In addition, the vast majority of TSC1 mutations result in protein truncation, while missense mutations have been reported only rarely (Northrup et al., 2011, Au et al., 2007). Therefore, based on the currently available information, it is unclear whether Thr300Ala is a disease-causing mutation or a rare benign variant. The variant is found in EPILEPSY panel(s).
Invitae RCV000642034 SCV000763687 uncertain significance Tuberous sclerosis 1 2019-09-16 criteria provided, single submitter clinical testing This sequence change replaces threonine with alanine at codon 300 of the TSC1 protein (p.Thr300Ala). The threonine residue is moderately conserved and there is a small physicochemical difference between threonine and alanine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with TSC1-related disease. ClinVar contains an entry for this variant (Variation ID: 207629). 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 tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.

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