ClinVar Miner

Submissions for variant NM_000548.5(TSC2):c.1397T>G (p.Leu466Arg) (rs45481199)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000482403 SCV000568290 likely pathogenic not provided 2017-03-14 criteria provided, single submitter clinical testing A variant that is likely pathogenic has been identified in the TSC2 gene. The c.1397 T>G variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The c.1397 T>G variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Several in-silico splice prediction models predict that c.1397 T>G creates a cryptic donor site which may supplant the natural donor site and lead to abnormal gene splicing. However, in the absence of RNA/functional studies, the actual effect of this sequence change in this individual is unknown. If the c.1397 T>G does not affect splicing, it will result in a L466R missense substitution. The L466R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. In addition, a different missense variant at the same residue (L466P) has been reported as a pathogenic variant in association with TSC (Hoogeveen-Westerveld et al., 2011, TSC2 LOVD). Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Tuberous sclerosis database (TSC2) RCV000043464 SCV000067274 not provided Tuberous sclerosis syndrome no assertion provided curation

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