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

dbSNP: rs45507199

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000190035	SCV000243708	pathogenic	not provided	2022-09-19	criteria provided, single submitter	clinical testing	Published functional studies demonstrate that R1743Q disrupts the TSC1-TSC2 complex (Coevoets et al., 2009; Hoogeveen-Westerveld et al., 2011); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 16981987, 22867869, 20165957, 18854862, 21309039, 10732801, 27406250, 16237225, 16114042, 17304050, 29801666, 30036593, 29655203, 31847710, 32555378, 32211034, 31447099, 33935721, 33532864, 34403804)
Athena Diagnostics	RCV000190035	SCV000255913	pathogenic	not provided	2020-06-02	criteria provided, single submitter	clinical testing	Predicted to have a damaging effect on the protein. Assessment of experimental evidence suggests this variant results in abnormal protein function. 2 de novo cases with parental identity confirmed, plus 2 unconfirmed cases.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000201149	SCV000544537	pathogenic	Tuberous sclerosis 2	2024-01-20	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1743 of the TSC2 protein (p.Arg1743Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with tuberous sclerosis (PMID: 10732801, 16114042, 18854862, 20165957, 21309039). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 49960). 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: 18854862, 21309039). This variant disrupts the p.Arg1743 amino acid residue in TSC2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10205261, 16981987, 18854862, 25782670). 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.
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: http://chromium.lovd.nl/LOVD2/TSC/variants.php?select_db=TSC2&action=search_all&search_Variant%2FDNA=c.5228G%3EA 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, Mass General Brigham 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
Molecular Biology Laboratory, Fundació Puigvert	RCV000201149	SCV001425281	likely pathogenic	Tuberous sclerosis 2	2020-02-01	criteria provided, single submitter	research
CeGaT Center for Human Genetics Tuebingen	RCV000190035	SCV001961556	pathogenic	not provided	2021-08-01	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000201149	SCV002041028	likely pathogenic	Tuberous sclerosis 2	2021-11-07	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002336163	SCV002645304	likely pathogenic	Hereditary cancer-predisposing syndrome	2018-06-22	criteria provided, single submitter	clinical testing	The p.R1743Q variant (also known as c.5228G>A), located in coding exon 40 of the TSC2 gene, results from a G to A substitution at nucleotide position 5228. The arginine at codon 1743 is replaced by glutamine, an amino acid with highly similar properties. This variant has been detected in multiple individual's with a clinical diagnosis of TSC (Gilbert JR et al. Neurogenetics. 1998 Aug;1:267-72; Au KS et al. Genet. Med. 2007 Feb;9:88-100; van Eeghen AM et al. Epilepsy Res. 2013 Jan;103:83-7). Functional studies have shown that the p.R1743Q variant leads to significantly reduced protein expression and disrupts the normal formation of the TSC1 and TSC2 complex (Coevoets R et al. Eur. J. Hum. Genet. 2009 Mar;17:301-10; Hoogeveen-Westerveld M et al. Hum. Mutat. 2011 Apr;32:424-35; Overwater IE et al. Eur. J. Hum. Genet. 2016 12;24:1688-1695). Of note, this variant is also referred to as p.R1720Q (c. 5177G>A) in some literature. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000190035	SCV004224090	pathogenic	not provided	2022-12-08	criteria provided, single submitter	clinical testing	PP3, PP4, PM2, PM5, PS3, PS4
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV000201149	SCV005417109	pathogenic	Tuberous sclerosis 2		criteria provided, single submitter	clinical testing	PM2_Supporting+PP3_Strong+PS4_Moderate+PP4+PS2_Moderate
Tuberous sclerosis database (TSC2)	RCV000043227	SCV000067028	not provided	Tuberous sclerosis syndrome		no assertion provided	curation
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000190035	SCV001741534	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000190035	SCV001972743	pathogenic	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004734600	SCV005362143	pathogenic	TSC2-related disorder	2024-05-13	no assertion criteria provided	clinical testing	The TSC2 c.5228G>A variant is predicted to result in the amino acid substitution p.Arg1743Gln. This variant (also described as p.Arg1720Gln) has been reported in multiple individuals with tuberous sclerosis (for example, see Gilbert et al. 1998. PubMed ID: 10732801; Kwiatkowski et al. 2015. PubMed ID: 25782670; Bąbol-Pokora et al. 2021. PubMed ID: 34403804; Ng et al. 2022. PubMed ID: 35918040) and has been observed to have arisen de novo in several patients (Rendtdorff et al. 2005. PubMed ID: 16114042; Qin et al. 2010. PubMed ID: 20165957; Overwater et al. 2016. PubMed ID: 27406250; Ding et al. 2020. PubMed ID: 32211034). In vitro functional studies have demonstrated that this variant leads to reduced protein expression, disrupted formation of the TSC1/TSC2 complex, and dysregulation of downstream signaling pathways (Coevoets et al. 2009. PubMed ID: 18854862; Hoogeveen-Westerveld et al. 2011. PubMed ID: 21309039; Overwater et al. 2016. PubMed ID: 27406250). This variant has not been reported in the gnomAD database and is interpreted as pathogenic by multiple submitters to ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/49960/). Of note, additional missense variants affecting the same amino acid residue (p.Arg1743Trp, p.Arg1743Pro) have been reported as disease-causing in individuals with tuberous sclerosis (Jones et al. 1999. PubMed ID: 10205261; Sancak et al. 2005. PubMed ID: 15798777; Ng et al. 2022. PubMed ID: 35918040). Taken together, this variant is interpreted as pathogenic.