ClinVar Genomic variation as it relates to human health

Observed in multiple unrelated patients from different ethnic backgrounds with tuberous sclerosis in published literature and well-curated databases and not observed in controls (Wilson et al., 1996; TSC2 LOVD); Published functional studies demonstrate 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); Missense variants in nearby residues reported in the Human Gene Mutation Database in individuals with tuberous sclerosis (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 15595939, 15483652, 22867869, 11741832, 21309039, 8824881, 27859028, 29655203, 30712878, 32211034, 32313033)

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.

The p.R611W pathogenic mutation (also known as c.1831C>T), located in coding exon 16 of the TSC2 gene, results from a C to T substitution at nucleotide position 1831. The arginine at codon 611 is replaced by tryptophan, an amino acid with dissimilar properties. This mutation has been detected in multiple individuals meeting diagnostic criteria for Tuberous sclerosis complex (TSC) (Ali M, et al. Acta Neurol. Scand. 2005; 111(1):54-63; Choy YS, et al. Ann. Hum. Genet. 1999; 63(Pt 5):383-91; Wilson PJ, et al. Hum. Mol. Genet. 1996; 5(2):249-56, Langkau N, et al. Eur. J. Pediatr. 2002; 161(7):393-402). In one functional study, authors showed that this mutation inhibits tuberin-hamartin binding, tuberin chaperone function, S6 and S6K phosphorylation and the stimulation of rheb GTPase activity (Nellist M, et al. Eur. J. Hum. Genet. 2005; 13(1):59-68; Nellist M, et al. Hum. Mol. Genet. 2001). Based on the supporting evidence, p.R611W is interpreted as a disease-causing mutation.

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg611 amino acid residue in TSC2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9463313, 10205261, 15595939, 17304050). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects TSC2 function (PMID: 11741832, 15483652, 15963462). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on TSC2 protein function. ClinVar contains an entry for this variant (Variation ID: 49643). This missense change has been observed in individual(s) with tuberous sclerosis (PMID: 8824881, 10205261, 10735580, 12111193, 15595939, 17304050, 22867869, 26540169). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 611 of the TSC2 protein (p.Arg611Trp).

This variant is considered pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 35712104, 36232477, 10205261, 32313033, 32917966, 27859028]. Functional studies indicate this variant impacts protein function [PMID: 11741832, 15483652, 15963462]. This variant is expected to disrupt protein structure [Myriad internal data].