rs45517412

Description

Not found in the total gnomAD dataset, and the data is high quality. Located in potentially critical domain of the protein. This variant occurs as the most likely explanation for disease in a significant number of internal cases, suggesting this variant is associated with disease. Assessment of experimental evidence suggests this variant results in abnormal protein function. 5 de novo cases with parental identity not confirmed, plus case with parental identity confirmed.

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1743 of the TSC2 protein (p.Arg1743Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with tuberous sclerosis, epilepsy and/or infantile spasms (PMID: 12111193, 16114042, 16981987, 22867869, 27174333, 29476190, 29500070, 29801666). In at least one individual the variant was observed to be de novo. This variant is also known as R1720W. ClinVar contains an entry for this variant (Variation ID: 49471). 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) performed at Invitae indicates that this missense variant is expected to disrupt TSC2 protein function. Experimental studies have shown that this missense change affects TSC2 function (PMID: 18854862, 21309039, 23955302). This variant disrupts the p.Arg1743 amino acid residue in TSC2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10732801, 16114042, 18854862, 20165957). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

The R1743W missense substitution in the TSC2 gene has been reported multiple times as a de novo pathogenic variant in association with TSC (Rendtorff et al., 2005; TSC2 LOVD). The R1743W substitution occurs at a conserved position in the RAP-GAP domain of the protein, and functional studies indicate that it disrupts the TSC1-TSC2 complex (Coevoets et al., 2009; Hoogeveen-Westerveld et al., 2011). Other missense variants at this position (R1743G/Q/P/L) have been published in association with TSC, supporting the functional importance of this region of the protein (TSC2 LOVD). The R1743W variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server).

The p.R1743W pathogenic mutation (also known as c.5227C>T), located in coding exon 40 of the TSC2 gene, results from a C to T substitution at nucleotide position 5227. The arginine at codon 1743 is replaced by tryptophan, an amino acid with dissimilar properties. This mutation has been described in two unrelated individuals with TSC who had infantile spasms and epilepsy (van Eeghen AM et al. Epilepsy Res. 2013;103(1):83-7). Another disease-causing mutation, p.R1743Q, has been described in the same codon. Analyses via in-cell western assay and transfection-based immunoblot assay showed reduced expression of the mutant p.R1743W and p.R1743Q TSC2 proteins compared to wild-type (Coevoets R et al. Eur. J. Hum. Genet. 2009;17(3):301-10, Hoogeveen-Westerveld M et al. Hum. Mutat. 2011;32(4):424-35). Based on the supporting evidence, p.R1743W is interpreted as a disease-causing mutation.