ClinVar Miner

Submissions for variant NM_000548.5(TSC2):c.3145G>A (p.Glu1049Lys) (rs796053492)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000562972 SCV000664608 uncertain significance Hereditary cancer-predisposing syndrome 2016-01-27 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Other data supporting pathogenic classification,Rarity in general population databases (dbsnp, esp, 1000 genomes),Insufficient or conflicting evidence,Co-occurence with a mutation in another gene that clearly explains a proband's phenotype,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
GeneDx RCV000766975 SCV000243686 uncertain significance not provided 2017-04-11 criteria provided, single submitter clinical testing The E1049K variant in the TSC2 gene was reported previously in a fetus with cardiac rhabdomyoma noted on ultrasound and confirmed at birth (Milunsky et al., 2009). However, no other features of TSC were noted in the patient, it is unknown whether there was a family history of TSC, and the parents were not tested for the variant. The E1049K variant 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 E1049K variant is a non-conservative amino acid substitution, which occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret E1049K as a variant of unknown significance.
Gharavi Laboratory,Columbia University RCV000766975 SCV000920701 uncertain significance not provided 2018-09-16 no assertion criteria provided research
Invitae RCV000470880 SCV000544336 uncertain significance Tuberous sclerosis 2 2018-05-29 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 1049 of the TSC2 protein (p.Glu1049Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with a cardiac rhabdomyoma (PMID: 19254590). It has also been observed in individuals with tuberous sclerosis in the Leiden Open-Source Variation Database (PMID: 21520333). However, in one of those individual a pathogenic allele was also identified in TSC1, which suggests that this c.3145G>A variant in TSC2 was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 207741). 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000190014 SCV000540605 uncertain significance not specified 2016-03-28 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Absent from ExAC. Detected in control and affected groups in autism study. Also published in study of pregnant women at risk for having child with TSC. No other pubs found.

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