ClinVar Miner

Submissions for variant NM_000548.5(TSC2):c.5138G>A (p.Arg1713His) (rs45517395)

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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 RCV000129852 SCV000184669 pathogenic Hereditary cancer-predisposing syndrome 2016-11-10 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: 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
GeneDx RCV000254730 SCV000322137 pathogenic not provided 2017-08-02 criteria provided, single submitter clinical testing The R1713H missense pathogenic variant has been reported previously in association with tuberous sclerosis complex (TSC) (Niemi et al., 2011, Hirfanoglu et al., 2010; TSC2 LOVD). Two individuals with R1713H were reported to have a horseshoe kidney and one had diaphragmatic hernia, representing atypical manifestations of TSC (Niemi et al., 2011). Functional studies indicate that R1713H is damaging to the protein (Hoogeveen-Westerveld et al. 2011). R1713H 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. This substitution alters a conserved position predicted to be within the Rap-GAP domain of the TSC2 protein. Missense variants at the same position (R1713P) and in nearby residues (P1709R, P1709L, A1712D, L1717P) have been reported in association with TSC (TSC2 LOVD; Stenson et al., 2014).
Invitae RCV000459221 SCV000544312 pathogenic Tuberous sclerosis 2 2017-12-04 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 1713 of the TSC2 protein (p.Arg1713His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with atypical phenotype presentation of tuberous sclerosis complex in a single family (PMID: 28127866). In addition, it has been reported in several individuals affected with tuberous sclerosis complex and an individual with hemimegalencephaly (PMID: 20399389, 21910228, 25599672). This variant is also known as R1690H in the literature. ClinVar contains an entry for this variant (Variation ID: 49930). Experimental studies have shown that this missense change is unstable and destabilizing (PMID: 21309039). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000763367 SCV000894063 pathogenic Lymphangiomyomatosis; Focal cortical dysplasia type II; Tuberous sclerosis 2 2018-10-31 criteria provided, single submitter clinical testing
Tuberous sclerosis database (TSC2) RCV000043197 SCV000066998 not provided Tuberous sclerosis syndrome no assertion provided curation

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