ClinVar Miner

Submissions for variant NM_000548.5(TSC2):c.2713C>T (p.Arg905Trp) (rs45517258)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000013213 SCV000255888 pathogenic Tuberous sclerosis 2 2014-09-23 criteria provided, single submitter clinical testing
GeneDx RCV000482063 SCV000567938 pathogenic not provided 2018-06-15 criteria provided, single submitter clinical testing The R905W missense variant in the TSC2 gene has been reported multiple times as a pathogenic variant in association with tuberous sclerosis (Au et al., 1998; van Eeghen et al., 2013; TSC2 LOVD). Functional studies indicate that R905W disrupts the TSC1–TSC2 complex and is pathogenic (Hoogeveen-Westerveld et al. 2011). R905W is a non-conservative amino acid substitution that occurs at a position that is highly conserved across species, and other missense variants at this position (R905G/Q) have also been published in association with TSC (TSC2 LOVD). Therefore, we interpret R905W as a pathogenic variant.
Invitae RCV000013213 SCV000644363 pathogenic Tuberous sclerosis 2 2019-02-15 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 905 of the TSC2 protein (p.Arg905Trp). 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 (rs45517258, ExAC no frequency). This variant has been reported in many individuals affected with tuberous sclerosis complex (PMID: 9463313, 22867869, 19259131, 17120248, 12015165), including several individuals in whom it was shown to be de novo (PMID: 9463313, 17120248). ClinVar contains an entry for this variant (Variation ID: 12404). Experimental studies have shown that this missense change alters mTOR activity in vitro (PMID: 21309039). A different missense substitution at this codon (p.Arg905Gln) has been determined to be pathogenic (PMID: 17120248, 22867869, 25432535, 9829910). 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.
Center for Human Genetics, Inc,Center for Human Genetics, Inc RCV000013213 SCV000782403 pathogenic Tuberous sclerosis 2 2016-11-01 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000042962 SCV000967769 pathogenic Tuberous sclerosis syndrome 2018-04-20 criteria provided, single submitter clinical testing The p.Arg905Trp variant in TSC2 has been previously reported in more than 25 ind ividuals with tuberous sclerosis complex, including at least one de novo occurre nce (TSC; Au 1998, Sancak 2005, Jansen 2006, Le Caignec 2009, Hoogeveen-Westerve ld 2011, van Eeghen 2013, Tuberous Sclerosis Project: http://tsc-project.partner, Tuberous sclerosis LOVD database: /TSC) and has also been reported by other clinical laboratories in ClinVar (Vari ation ID: 12404). In vitro functional studies provide some evidence that the p. Arg905Trp variant may impact protein function (Jansen 2006, Hoogeveen-Westerveld 2011). This variant was absent from large population studies. Computational pr ediction tools and conservation analysis suggest that the p.Arg905Trp variant ma y impact the protein. Another variant at the same amino acid position (p.Arg905G ln) has been reported in individuals with TSC (Beauchamp 1998, Yamamoto 2002, Ja nsen 2006, van Eeghen 2013, Tyburczy 2015, Tuberous Sclerosis Project: http://ts, suggesting that changes at this amino acid po sition are not tolerated. In summary, this variant meets criteria to be classif ied as pathogenic for TSC in an autosomal dominant manner based upon presence in multiple affected individuals, including a de novo occurrence, absence from the general population and functional and computational evidence. ACMG/AMP Criteria applied: PS4, PM6, PM2, PP3, PS3_Supporting.
OMIM RCV000013213 SCV000033460 pathogenic Tuberous sclerosis 2 2009-09-01 no assertion criteria provided literature only
Tuberous sclerosis database (TSC2) RCV000042962 SCV000066759 not provided Tuberous sclerosis syndrome no assertion provided curation

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