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

dbSNP: rs45517258

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics	RCV000013213	SCV000255888	pathogenic	Tuberous sclerosis 2	2014-09-23	criteria provided, single submitter	clinical testing
GeneDx	RCV000482063	SCV000567938	pathogenic	not provided	2021-12-17	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect on the TSC1-TSC2 complex (Hoogeveen-Westerveld et al. 2011); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 31447099, 25782670, 12015165, 19259131, 17304050, 14641237, 9463313, 22867869, 17120248, 22805177, 10205261, 23081885, 29196670, 31855466, 21309039)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000013213	SCV000644363	pathogenic	Tuberous sclerosis 2	2024-01-09	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 905 of the TSC2 protein (p.Arg905Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with tuberous sclerosis complex (PMID: 9463313, 12015165, 17120248, 19259131, 22867869). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 12404). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on TSC2 protein function. Experimental studies have shown that this missense change affects TSC2 function (PMID: 21309039). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the p.Arg905 amino acid residue in TSC2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9829910, 17120248, 22867869, 25432535). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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, Mass General Brigham 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 s.org/index.htm, Tuberous sclerosis LOVD database: http://chromium.lovd.nl/LOVD2 /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 c-project.partners.org/index.htm), 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000482063	SCV001714528	pathogenic	not provided	2020-02-11	criteria provided, single submitter	clinical testing	PS3, PS4_moderate, PM2, PM5, PM6, PP4, PP5
Fulgent Genetics, Fulgent Genetics	RCV001536008	SCV001752687	pathogenic	Lymphangiomyomatosis; Isolated focal cortical dysplasia type II; Tuberous sclerosis 2	2021-06-30	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000013213	SCV002040958	pathogenic	Tuberous sclerosis 2	2021-11-07	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV000013213	SCV002556836	pathogenic	Tuberous sclerosis 2	2021-12-22	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002426499	SCV002741408	pathogenic	Hereditary cancer-predisposing syndrome	2022-11-22	criteria provided, single submitter	clinical testing	The p.R905W pathogenic mutation (also known as c.2713C>T), located in coding exon 23 of the TSC2 gene, results from a C to T substitution at nucleotide position 2713. The arginine at codon 905 is replaced by tryptophan, an amino acid with dissimilar properties. The p.R905W pathogenic variant has been reported as a recurrent de novo alteration in patients diagnosed with TSC (Au KS et al. Am. J. Hum. Genet., 1998 Feb;62:286-94; Jansen AC et al. Ann. Neurol. 2006 Nov;60(5):528-39; Le Caignec C et al. Eur. J. Hum. Genet., 2009 Sep;17:1165-70; http://www.lovd.nl/TSC2). Two additional mutations at codon 905 (p.R905Q and p.R905G) have been reported in numerous TSC families to date. Functional studies indicate that p.R905W disrupts tuberin activity and is pathogenic (Jansen AC et al. Ann. Neurol. 2006 Nov;60(5):528-39; Hoogeveen-Westerveld M et al. Hum. Mutat., 2011 Apr;32:424-35). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the available evidence, this alteration is interpreted as a disease-causing mutation.
Revvity Omics, Revvity	RCV000013213	SCV003823724	pathogenic	Tuberous sclerosis 2	2022-10-17	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000013213	SCV004018408	pathogenic	Tuberous sclerosis 2	2023-03-22	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 17120248, 29458892, 32917966, 14641237, 29196670]. Functional studies indicate this variant impacts protein function [PMID: 17120248, 21309039]. This variant is expected to disrupt protein structure [Myriad internal data].
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
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000482063	SCV001744750	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000482063	SCV001964629	pathogenic	not provided		no assertion criteria provided	clinical testing