ClinVar Miner

Submissions for variant NM_000368.4(TSC1):c.2026T>A (p.Trp676Arg) (rs748901883)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000189817 SCV000243469 uncertain significance not provided 2018-05-21 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the TSC1 gene. The W676R variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The W676R variant is observed in 2/66348 (0.003%) alleles from individuals of European background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). TheW676R 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. In silico analysis predicts this variant is probably damaging to the protein structure/function. However, the vast majority of TSC1 pathogenic variants result in protein truncation, while missense variants have been reported only rarely (Northrup et al., 2011; Au et al., 2007). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000476132 SCV000552380 uncertain significance Tuberous sclerosis 1 2018-03-06 criteria provided, single submitter clinical testing This sequence change replaces tryptophan with arginine at codon 676 of the TSC1 protein (p.Trp676Arg). The tryptophan residue is moderately conserved and there is a moderate physicochemical difference between tryptophan and arginine. This variant is present in population databases (rs748901883, ExAC 0.003%). This variant has not been reported in the literature in individuals with TSC1-related disease. ClinVar contains an entry for this variant (Variation ID: 207613). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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