ClinVar Miner

Submissions for variant NM_000548.5(TSC2):c.1831C>T (p.Arg611Trp) (rs45469298)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000189989 SCV000243660 pathogenic not provided 2018-05-22 criteria provided, single submitter clinical testing The R611W substitution in the TSC2 gene is a recurrent pathogenic variant that has been reported in multiple unrelated patients with a clinical diagnosis of tuberous sclerosis (Wilson et al., 1996; TSC2 LOVD). This substitution occurs at a conserved position in the protein, and multiple other missense variants (R611G/P/Q) have been reported at this residue in association with TSC (Stenson et al., 2014). Functional studies indicate this position is critical to the chaperone function of the tuberin protein, and substitutions at this position disrupt tuberin-hamartin complex formation (Nellist et al., 2001; Nellist et al., 2005). Additionally, R611W 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.
Ambry Genetics RCV000491813 SCV000579594 pathogenic Hereditary cancer-predisposing syndrome 2016-06-17 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Confirmed de novo alteration in the setting of a new disease (appropriate phenotype) in the family,Structural Evidence,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
Invitae RCV000539587 SCV000644288 pathogenic Tuberous sclerosis 2 2018-09-12 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 611 of the TSC2 protein (p.Arg611Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is not present in population databases (rs45469298, ExAC no frequency). This variant has been reported in the literature in multiple individuals affected with tuberous sclerosis (PMID: 8824881, 26540169, 17304050, 15595939, 22867869, 12111193, 10735580, 10205261). ClinVar contains an entry for this variant (Variation ID: 49643). Experimental studies have shown that this missense change disrupts TSC2 protein function by disrupting tuberin-hamartin interactions in vitro and by inhibiting the phophorylation of tuberin by PKB in human and mouse embryonic fibroblasts (PMID: 15483652, 11741832, 15963462). A different missense substitution at this codon (p.Arg611Gln) has been determined to be pathogenic (PMID: 9463313, 17304050, 15595939, 10205261). This suggests that the arginine residue is critical for TSC2 protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV000768117 SCV000899050 pathogenic Lymphangiomyomatosis; Focal cortical dysplasia type II; Tuberous sclerosis 2 2018-04-27 criteria provided, single submitter clinical testing TSC2 NM_000548.4 exon 17 p.Arg611Trp (c.1831C>T): This variant has been well reported in the literature, described in several individuals with tuberous sclerosis, at least one of whom was reported to be de novo (Wilson 1996 PMID:8824881, Choy 1999 PMID:10735580, Jones 1999 PMID:10205261, Ali 2005 PMID:15595939, Au 2007 PMID:17304050, van Eeghen 2013 PMID:22867869, Tyburczy 2015 PMID:26540169). This variant is not present in large control databases. This variant is present in ClinVar, with several labs classifying this variant as pathogenic (Variation ID:49643). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In addition, functional studies also predict that this variant will impact the protein (Nellist 2001 PMID:11741832, Nellist 2005 PMID:15483652). Other variants at this same codon (p.Arg611Gln, p.Arg611Gly) have been reported in association with disease in the literature, supporting that this region has significance. In summary, this variant is classified as pathogenic.
Tuberous sclerosis database (TSC2) RCV000042905 SCV000066701 not provided Tuberous sclerosis syndrome no assertion provided curation

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