ClinVar Miner

Submissions for variant NM_000368.4(TSC1):c.2375A>G (p.Gln792Arg) (rs796053460)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000189855 SCV000243508 uncertain significance not provided 2012-06-08 criteria provided, single submitter clinical testing p.Gln792Arg (CAG>CGG): c.2375 A>G in exon 18 of the TSC1 gene (NM_000368.3). The nGln792Arg 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 Gln792Arg in approximately 5,000 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 an uncharged Glutamine residue is replaced by a positively charged Arginine residue. Gln792Arg alters a position that is highly conserved in the hamartin protein but is not conserved in related proteins, and multiple in silico models predict that Lys30Arg is benign. Additionally, 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). These findings suggest that Gln792Arg is likely a rare benign variant; however, the possibility that Gln792Arg is disease-causing cannot be excluded at present. The variant is found in INFANT-EPI panel(s).
Invitae RCV000558000 SCV000641565 uncertain significance Tuberous sclerosis 1 2019-06-26 criteria provided, single submitter clinical testing This sequence change replaces glutamine with arginine at codon 792 of the TSC1 protein (p.Gln792Arg). The glutamine residue is moderately conserved and there is a small physicochemical difference between glutamine and arginine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a TSC1-related disease. ClinVar contains an entry for this variant (Variation ID: 207636). 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. In summary, this variant is a rare missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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