ClinVar Miner

Submissions for variant NM_000548.5(TSC2):c.4646A>G (p.Tyr1549Cys) (rs45517355)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000412893 SCV000491162 likely pathogenic not provided 2016-04-18 criteria provided, single submitter clinical testing A Y1549C variant that is likely pathogenic has been identified in the TSC2 gene. The Y1549C variant has been reported previously as an assumed pathogenic variant in individuals with TSC (Au et al., 1998; vanEeghen et al., 2013). It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The Y1549C 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 alters a conserved position in mammals predicted to be within the GAP-related domain of the tuberin protein, (Gumbinger et al., 2009 ), and multiple missense variants at the same and nearby residues have been reported in Human Gene Mutation Database in association with tuberous sclerosis (Stenson et al., 2014), supporting the functional importance of this region of the protein. Additionally, in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Invitae RCV001036250 SCV001199602 pathogenic Tuberous sclerosis 2 2019-12-27 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 1549 of the TSC2 protein (p.Tyr1549Cys). The tyrosine residue is moderately 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 been observed in individual(s) with tuberous sclerosis complex (PMID:9463313, 28178598, Invitae). In at least one individual the variant was observed to be de novo. This variant is also known as 4577A>G, Tyr1526Cys in the literature. ClinVar contains an entry for this variant (Variation ID: 49479). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant disrupts the p.Tyr1549 amino acid residue in TSC2. Other variant(s) that disrupt this residue have been observed in individuals with TSC2-related conditions (PMID: 11112665), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Tuberous sclerosis database (TSC2) RCV000042739 SCV000066534 not provided Tuberous sclerosis syndrome no assertion provided curation

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