ClinVar Miner

Submissions for variant NM_000548.5(TSC2):c.5228G>A (p.Arg1743Gln) (rs45507199)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000190035 SCV000243708 pathogenic not provided 2018-07-16 criteria provided, single submitter clinical testing The R1743Q missense variant in the TSC2 gene has been reported multiple times as a pathogenic variant in association with tuberous sclerosis complex (Au et al., 2007; Hoogeveen-Westerveld et al., 2011; TSC2 LOVD). Functional studies indicate that R1743Q disrupts the TSC1 – TSC2 complex (Coevoets et al., 2009; Hoogeveen-Westerveld et al., 2011). The R1743Q substitution occurs at a position in the RAP-GAP domain of the protein that is highly conserved across species, and other missense variants at this position (R1743W/P) have also been published in association with TSC (TSC2 LOVD). The R1743Q variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server).
Athena Diagnostics Inc RCV000201149 SCV000255913 pathogenic Tuberous sclerosis 2 2014-12-15 criteria provided, single submitter clinical testing
Invitae RCV000201149 SCV000544537 pathogenic Tuberous sclerosis 2 2019-12-31 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 1743 of the TSC2 protein (p.Arg1743Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals affected with tuberous sclerosis and has been shown to arise de novo (PMID: 10732801, 20165957, 21309039, 18854862, 16114042). In addition, different missense substitutions at this codon (p.Arg1743Pro, p.Arg1743Trp, and p.Arg1743Gly) are reported to be deleterious (PMID: 18854862, 16981987, 10205261, 25782670). This indicates that the arginine residue is important for TSC2 protein function. This variant is also known as c.5177G>A and p.Arg1720Gln in the literature. Experimental studies have shown that this missense change disrupts the TSC1-TSC2 complex formation and its further downstream signaling (PMID: 18854862, 21309039). For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000190035 SCV000884760 pathogenic not provided 2018-06-09 criteria provided, single submitter clinical testing The TSC2 c.5228G>A; p.Arg1743Gln variant (rs45507199), also known as R1720Q, is reported in multiple individuals affected with tuberous sclerosis complex and has been reported as a de novo variant (Coevoets 2009, Hoogeveen-Westerveld 2011, Overwater 2016, Qin 2010, see LOVD TSC2 database). Functional analyses show the variant disrupts the TSC1-TSC2 complex and affects downstream signaling (Coevoets 2009, Hoogeveen-Westerveld 2011, Overwater 2016). This variant is classified as pathogenic in ClinVar (Variation ID: 49960), as well as another variant at this codon (p.Arg1743Trp, Variation ID: 49471). The p.Arg1743Gln variant is absent from the general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. The arginine at codon 1743 is highly conserved and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, the p.Arg1743Gln variant is considered to be pathogenic. REFERENCES LOVD TSC2 database link: Coevoets R et al. A reliable cell-based assay for testing unclassified TSC2 gene variants. Eur J Hum Genet. 2009 Mar;17(3):301-10. Hoogeveen-Westerveld M et al. Functional assessment of variants in the TSC1 and TSC2 genes identified in individuals with Tuberous Sclerosis Complex. Hum Mutat. 2011 Apr;32(4):424-35. Overwater IE et al. Genotype and brain pathology phenotype in children with tuberous sclerosis complex. Eur J Hum Genet. 2016 Dec;24(12):1688-1695. Qin W et al. Ultra deep sequencing detects a low rate of mosaic mutations in tuberous sclerosis complex. Hum Genet. 2010 Mar;127(5):573-82.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000043227 SCV000967767 pathogenic Tuberous sclerosis syndrome 2018-05-04 criteria provided, single submitter clinical testing The Arg1743Gln variant in TSC2 was absent from large population studies but has been reported in at least 10 individuals with tuberous sclerosis (Gilbert 1998, Rendtorff 2005, Hung 2006, Qin 2010, van Eeghen 2013, Overwater 2016). In 2 of those individuals, the variant was reported to have occurred de novo (Rendtorff 2005, Overwater 2016). Different missense substitutions at this codon (p.Arg1743 Pro), (p.Arg1743Trp), and (p.Arg1743Gly) have been reported in individuals with tuberous sclerosis (HGMD database). In vitro functional studies provide some evi dence that the p.Arg1743Gln variant may impact protein function (Coevoets 2009, Hoogeveen-Westerveld 2011, Overwater 2016). However, these types of assays may n ot accurately represent biological function. Computational prediction tools and conservation analysis suggest that the p.Arg1743Gln variant may impact the prot ein, though this information is not predictive enough to determine pathogenicity . In summary, this variant meets criteria to be classified as pathogenic for tub erous sclerosis in an autosomal dominant manner based upon presence in multiple affected individuals, absence from controls, in vitro functional evidence, and p redicted impact on protein. ACMG/AMP Criteria applied: PS2; PM5; PS4_Moderate; P M2; PS3_Moderate.
Division of Genomic Medicine, Department of Advanced Medicine, Medical Research Institute,Kanazawa Medical University RCV000201149 SCV001423576 pathogenic Tuberous sclerosis 2 2020-07-10 criteria provided, single submitter clinical testing
Tuberous sclerosis database (TSC2) RCV000043227 SCV000067028 not provided Tuberous sclerosis syndrome no assertion provided curation

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