Submissions for variant NM_000548.5(TSC2):c.2714G>A (p.Arg905Gln)

dbSNP: rs45517259

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000221069	SCV000275601	pathogenic	Hereditary cancer-predisposing syndrome	2023-06-05	criteria provided, single submitter	clinical testing	The p.R905Q pathogenic mutation (also known as c.2714G>A), located in coding exon 23 of the TSC2 gene, results from a G to A substitution at nucleotide position 2714. The arginine at codon 905 is replaced by glutamine, an amino acid with highly similar properties.The p.R905Q mutation and two additional mutations at codon 905 (p.R905W and p.R905G) have been reported in numerous TSC families to date (http://www.lovd.nl/TSC2; Stenson et al. The Human Gene Mutation Database (HGMD®): 2003 Update. Hum Mutat. 2003;21:577-581). In one large study of TSC2 codon 905 alterations, p.R905Q was associated with a milder clinical presentation compared to p.R905W and p.R905G (Jansen AC et al. Ann. Neurol. 2006 Nov;60(5):528-39). Phenotype data from 40 p.R905Q-carriers across 6 families revealed the following frequency of clinical features: skin lesions (95%), seizures/epilepsy (67%), brain lesions (50%), cognitive impairment (18%), renal lesions (15%), and rhabdomyoma (7%). In one large kindred, of 12 p.R905Q-positive individuals with thorough diagnostic workup: 5 had definite TSC, 4 probable TSC, 1 possible TSC, and 2 did not satisfy TSC diagnostic criteria. Functional analyses have shown that, despite allowing proper tuberin-hamartin formation, the p.R905Q mutation impairs S6K phosphorylation inhibition compared to wild type TSC2 which may lead to more mild presentation of symptoms (Nellist M et al. Hum. Mol. Genet. 2001 Dec;10(25):2889-98; Hoogeveen-Westerveld M et al. Hum. Mutat. 2011 Apr;32(4):424-35; Wentink M et al. Clin. Genet. 2012 May;81:453-61). Based on the available evidence, p.R905Q is classified as a pathogenic mutation associated with reduced penetrance compared to other TSC2 mutations.
GeneDx	RCV000255572	SCV000321981	pathogenic	not provided	2023-03-14	criteria provided, single submitter	clinical testing	While some individuals with the R905Q variant are reported to meet clinical diagnostic criteria for definite TSC, others have been reported to have a milder clinical presentation characterized primarily by the presence of skin findings with or without epilepsy (Jansen et al., 2006; Wentink et al., 2011; van Eeghen et al. 2013); Published functional studies demonstrate a damaging effect: disrupts the activity of the TSC1-TSC2 binding complex, without disrupting the TSC1-TSC2 binding, which may explain a milder phenotype (Hoogeveen-Westerveld et al., 2011; Jansen et al., 2006); 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: 15483652, 15798777, 22867869, 11741832, 21332470, 10533067, 16464865, 15963462, 29655203, 25432535, 11112665, 9829910, 17120248, 21309039, 30787465, 31440721, 32917966)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000013212	SCV000644364	pathogenic	Tuberous sclerosis 2	2023-12-11	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 905 of the TSC2 protein (p.Arg905Gln). 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: 9829910, 17120248, 22867869, 25432535). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12403). 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: 16464865, 21309039). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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: 17120248). 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.
CeGaT Center for Human Genetics Tuebingen	RCV000255572	SCV001247495	pathogenic	not provided	2018-07-01	criteria provided, single submitter	clinical testing
Division of Genomic Medicine, Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University	RCV000013212	SCV001423567	pathogenic	Tuberous sclerosis 2	2020-07-10	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000013212	SCV002040959	pathogenic	Tuberous sclerosis 2	2021-11-07	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002482858	SCV002791643	pathogenic	Lymphangiomyomatosis; Isolated focal cortical dysplasia type II; Tuberous sclerosis 2	2021-09-09	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004532330	SCV004115530	pathogenic	TSC2-related disorder	2023-10-11	criteria provided, single submitter	clinical testing	The TSC2 c.2714G>A variant is predicted to result in the amino acid substitution p.Arg905Gln. This variant has been reported in multiple unrelated patients with tuberous sclerosis complex (TSC) (Beauchamp et al. 1998. PubMed ID: 9829910; Niida et al. 1999. PubMed ID: 10533067; Jansen et al. 2006. PubMed ID: 17120248; van Eeghen et al. 2013. PubMed ID: 22867869). It has been suggested that this variant is associated with a milder phenotype than is typically seen in patients with TSC (Jansen et al. 2006. PubMed ID: 17120248; van Eeghen et al. 2013. PubMed ID: 22867869).. This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant has been interpreted as pathogenic by multiple independent submitters in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/12403/). This variant is interpreted as pathogenic.
Myriad Genetics, Inc.	RCV000013212	SCV004189836	likely pathogenic	Tuberous sclerosis 2	2023-07-18	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 17120248, 9829910, 29659200, 25432535].
All of Us Research Program, National Institutes of Health	RCV000042875	SCV004842741	pathogenic	Tuberous sclerosis syndrome	2023-12-18	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 905 of the TSC2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant is partially defective for inhibition of pS6K (T389), inhibition of pS6, and RHEB GAP activity when compared to wild-type TSC2 (PMID: 15483652, 16464865, 17120248, 21309039, 21332470). This variant has been reported in numerous individuals affected with tuberous sclerosis complex (PMID: 17120248, 9829910, 11112665, 17120248, 22867869). It has also been shown that this variant segregates with disease in multiple families. (PMID: 17120248). The variant has also been associated with milder disease phenotypes (PMID: 17120248, 21332470, 20301399). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. This variant may be hypomorphic and may display reduced penetrance relative to typical pathogenic TSC2 variants.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000042875	SCV005045785	pathogenic	Tuberous sclerosis syndrome	2023-10-23	criteria provided, single submitter	clinical testing	The c.2714G>A (p.Arg905Gln) variant in the TSC2 gene is located in exon 24 and replaces arginine at codon 905 with glutamine. This variant has been observed in individuals with tuberous sclerosis complex (PMID: 9829910, 17120248, 21332470, 22867869, 25432535). This variant has also been reported to be associated with milder disease spectrum (PMID: 17120248, 21332470, 22867869). Functional studies have shown that this variant has a damaging effect on TSC2 function (PMID: 16464865, 17120248, 21309039, 21332470). This variant has been reported as pathogenic in ClinVar by multiple submitters (ID: 12403). Another variant affecting the same amino acid residue, c.2713C>T (p.Arg905Trp) has also been reported as pathogenic in ClinVar (ID: 12404). Computational evidence supports a deleterious effect on the gene or gene product (REVEL score: 0.959). This variant is rare (0/250752 chromosomes) in the general population database (gnomAD). Therefore, the c.2714G>A (p.Arg905Gln) variant in the TSC2 gene is classified as pathogenic.
Breakthrough Genomics, Breakthrough Genomics	RCV000013212	SCV005088729	pathogenic	Tuberous sclerosis 2	2021-07-08	criteria provided, single submitter	clinical testing	This variant was previously reported in patients diagnosed with tuberous sclerosis complex (TSC) and reported to segregate with the disease in several families [PMID: 17120248, 22867869, 25432535, 9829910]. Functional studies demonstrate that this variant results in decreased TSC2 activity and destabilize the protein due to increased HERC1 binding and ubiquitination [PMID: 21309039, 16464865]. It disrupts the activity of the TSC1-TSC2 binding complex without disrupting the TSC1-TSC2 binding [PMID:11741832, 21332470, 15963462].
OMIM	RCV000013212	SCV000033459	pathogenic	Tuberous sclerosis 2	2006-11-01	no assertion criteria provided	literature only
Tuberous sclerosis database (TSC2)	RCV000042875	SCV000066671	not provided	Tuberous sclerosis syndrome		no assertion provided	curation
GeneReviews	RCV000013212	SCV000245751	not provided	Tuberous sclerosis 2		no assertion provided	literature only