ClinVar Miner

Submissions for variant NM_000368.4(TSC1):c.1811A>G (p.Tyr604Cys) (rs1057522817)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000436287 SCV000529612 uncertain significance not provided 2016-07-14 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the TSC1 gene. The Y604C variant has not been publishedas a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was not observed inapproximately 6,500 individuals of European and African American ancestry in the NHLBI Exome SequencingProject, indicating it is not a common benign variant in these populations. The Y604C variant is a non-conservativeamino 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, and insilico analysis predicts this variant is probably damaging to the protein structure/function. However, the vast majorityof 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 whetherthis variant is a pathogenic variant or a rare benign variant.
Invitae RCV000548490 SCV000641524 uncertain significance Tuberous sclerosis 1 2018-10-01 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 604 of the TSC1 protein (p.Tyr604Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with TSC1-related disease. ClinVar contains an entry for this variant (Variation ID: 387536). 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: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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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