ClinVar Miner

Submissions for variant NM_000548.5(TSC2):c.5227C>T (p.Arg1743Trp) (rs45517412)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000190076 SCV000243751 pathogenic not provided 2019-01-18 criteria provided, single submitter clinical testing The R1743W missense substitution in the TSC2 gene has been reported multiple times as a de novo pathogenic variant in association with TSC (Rendtorff et al., 2005; TSC2 LOVD). The R1743W substitution occurs at a conserved position in the RAP-GAP domain of the protein, and functional studies indicate that it disrupts the TSC1-TSC2 complex (Coevoets et al., 2009; Hoogeveen-Westerveld et al., 2011). Other missense variants at this position (R1743G/Q/P/L) have been published in association with TSC, supporting the functional importance of this region of the protein (TSC2 LOVD). The R1743W variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server).
Athena Diagnostics Inc RCV000201065 SCV000255912 pathogenic Tuberous sclerosis 2 2014-04-09 criteria provided, single submitter clinical testing
Ambry Genetics RCV000491169 SCV000579598 pathogenic Hereditary cancer-predisposing syndrome 2016-06-19 criteria provided, single submitter clinical testing Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Deficient protein function in appropriate functional assay(s);Well-characterized mutation at same position
Center of Genomic medicine, Geneva,University Hospital of Geneva RCV000201065 SCV000598110 pathogenic Tuberous sclerosis 2 2016-12-06 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000190076 SCV000615923 pathogenic not provided 2018-08-01 criteria provided, single submitter clinical testing
Invitae RCV000201065 SCV000644619 pathogenic Tuberous sclerosis 2 2019-07-01 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 1743 of the TSC2 protein (p.Arg1743Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals affected with tuberous sclerosis, including de novo observations (PMID: 12111193, 16114042, 16981987, 27174333, 29476190, 29801666, 29500070). It has also been reported in two individuals affected with epilepsy and infantile spasms (PMID: 22867869). This variant is also known as R1720W in the literature. ClinVar contains an entry for this variant (Variation ID: 49471). Experimental studies have shown that this missense change affects the protein-protein interaction of TSC2 with PEX5 and reduces the ability of TSC2 protein to inhibit the downstream TORC1 pathway (PMID: 18854862, 21309039, 23955302). A different missense substitution at this codon (p.Arg1743Gln) has been determined to be pathogenic (PMID: 10732801, 16114042, 18854862, 20165957). This suggests that the arginine residue is critical for TSC2 protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000763368 SCV000894064 pathogenic Lymphangiomyomatosis; Focal cortical dysplasia type II; Tuberous sclerosis 2 2018-10-31 criteria provided, single submitter clinical testing
Division of Genomic Medicine, Department of Advanced Medicine, Medical Research Institute,Kanazawa Medical University RCV000201065 SCV001423575 pathogenic Tuberous sclerosis 2 2020-07-10 criteria provided, single submitter clinical testing
Tuberous sclerosis database (TSC2) RCV000042731 SCV000066526 not provided Tuberous sclerosis syndrome no assertion provided curation

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