ClinVar Miner

Submissions for variant NM_000548.5(TSC2):c.2714G>A (p.Arg905Gln) (rs45517259)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000221069 SCV000275601 pathogenic Hereditary cancer-predisposing syndrome 2017-01-20 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Deficient protein function in appropriate functional assay(s),Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Good segregation with disease (lod 1.5-3 = 5-9 meioses),Well-characterized mutation at same position
GeneDx RCV000255572 SCV000321981 pathogenic not provided 2017-05-11 criteria provided, single submitter clinical testing The R905Q missense pathogenic variant in the TSC2 gene has been reported previously in multiple families with tuberous sclerosis complex (TSC) (Beauchamp et al., 1998; Jansen et al., 2006; TSC2 LOVD). While some individuals with the R905Q variant are reported to meet clinical diagnostic criteria for definite TSC, others have been reported to have a milder clinical presentation characterized primarily by the presence of skin findings with or without epilepsy (Jansen et al., 2006; Wentink et al., 2011). Functional studies demonstrate that R905Q disrupts the activity of the TSC1-TSC2 binding complex, without disrupting the TSC1-TSC2 binding, which may explain a milder phenotype (Hoogeveen-Westerveld et al., 2011; Jansen et al., 2006). The R905Q variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). R905Q is a semi-conservative amino acid substitution, which occurs at a position that is highly conserved across species. Therefore the presence of R905Q is consistent with the diagnosis of TSC in this individual.
Invitae RCV000013212 SCV000644364 pathogenic Tuberous sclerosis 2 2018-11-20 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 905 of the TSC2 protein (p.Arg905Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with tuberous sclerosis complex (TSC) in more than 20 individuals from several families (PMID: 17120248, 22867869, 25432535, 9829910). A different missense substitution at this codon (p.Arg905Trp) has been determined to be pathogenic (PMID: 17120248). This suggests that the arginine residue is critical for TSC2 protein function and that other missense substitutions at this position may also be pathogenic. Experimental studies of this missense change indicate that it results in decreased TSC2 activity (PMID: 21309039). While multiple studies have demonstrated that the p.Arg905Gln substitution does not directly disrupt the tuberin-hamartin interaction or alter phosphorlation of the TSC2 protein in vitro (PMID: 11741832, 21332470, 15963462), this missense change appears to destablize the TSC2 protein due to increased HERC1 binding and ubiquitination (PMID: 16464865). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000013212 SCV000033459 pathogenic Tuberous sclerosis 2 2006-11-01 no assertion criteria provided literature only
Tuberous sclerosis database (TSC2) RCV000042875 SCV000066671 not provided Tuberous sclerosis syndrome no assertion provided curation
GeneReviews RCV000013212 SCV000245751 pathogenic Tuberous sclerosis 2 2015-09-03 no assertion criteria provided literature only

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