ClinVar Miner

Submissions for variant NM_000548.5(TSC2):c.5137C>A (p.Arg1713Ser)

dbSNP: rs759420443
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000487488 SCV000574717 uncertain significance Hereditary cancer-predisposing syndrome 2017-03-01 criteria provided, single submitter clinical testing The p.R1713S variant (also known as c.5137C>A), located in coding exon 39 of the TSC2 gene, results from a C to A substitution at nucleotide position 5137. The arginine at codon 1713 is replaced by serine, an amino acid with dissimilar properties. A similar alteration at this position p.R1713H, has been reported in multiple individuals meeting clinical diagnostic criteria for tuberous sclerosis complex (TSC), including an individual with infantile-onset TSC and two unrelated children with classic TSC phenotypes and positive family histories (Hirfanoglu T and Gupta A Pediatr. Neurol. 2010; 42:343-7; Niemi AK et al. Am. J. Med. Genet. 2011; 155A:2534-7). Functional analyses of p.R1713H demonstrated significant associated reductions in both TSC2 stability and TSC1 protein levels compared to wild-type (Hoogeveen-Westerveld M et al. Hum. Mutat. 2011; 32:424-35). Another alteration at the same codon, p.R1713P, has been reported as a pathogenic de novo mutation in an individual with sporadic TSC (Leiden Open Variation Database (LOVD) [available from http://chromium.liacs.nl/LOVD2/TSC/home.php?select_db=TSC2]).This amino acid position is highly conserved in available vertebrate species. In addition, p.R1713S is predicted to be probably damaging and deleterious by PolyPhen and SIFT in silico analyses, respectively. This variant has been detected in a proband sufficiently examined for tuberous sclerosis who does not have any disease symptoms (Ambry internal data). Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000810759 SCV000950992 uncertain significance Tuberous sclerosis 2 2020-05-27 criteria provided, single submitter clinical testing 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. This variant disrupts the p.Arg1713 amino acid residue in TSC2. Other variant(s) that disrupt this residue have been observed in individuals with TSC2-related conditions (PMID:28127866, 20399389, 21910228, 25599672), suggesting that it may be a clinically significant residue. 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. 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: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with TSC2-related conditions. ClinVar contains an entry for this variant (Variation ID: 424872). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with serine at codon 1713 of the TSC2 protein (p.Arg1713Ser). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and serine.
Genome-Nilou Lab RCV000810759 SCV002040870 uncertain significance Tuberous sclerosis 2 2021-11-07 criteria provided, single submitter clinical testing

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