rs45517259

chr16-2076142-G-Achr16-2076142-G-Cchr16-2076142-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000548.5(TSC2):c.2714G>A(p.Arg905Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R905W) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TSC2 NM_000548.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11 O:2
• Conservation: PhyloP100: 9.92

Genes affected

TSC2 (HGNC:12363): (TSC complex subunit 2) This gene is a tumor suppressor gene that encodes the growth inhibitory protein tuberin. Tuberin interacts with hamartin to form the TSC protein complex which functions in the control of cell growth. This TSC protein complex negatively regulates mammalian target of rapamycin complex 1 (mTORC1) signaling which is a major regulator of anabolic cell growth. Mutations in this gene have been associated with tuberous sclerosis and lymphangioleiomyomatosis. [provided by RefSeq, May 2022]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 15 uncertain in NM_000548.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-2076141-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 12404.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.983
• PP5: Variant 16-2076142-G-A is Pathogenic according to our data. Variant chr16-2076142-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 12403.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2076142-G-A is described in Lovd as [Pathogenic]. Variant chr16-2076142-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSC2	NM_000548.5	c.2714G>A	p.Arg905Gln	missense_variant	24/42	ENST00000219476.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSC2	ENST00000219476.9	c.2714G>A	p.Arg905Gln	missense_variant	24/42	5	NM_000548.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000603 Hom.: 0

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tuberous sclerosis 2 Pathogenic:5 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 11, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Division of Genomic Medicine, Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University	Jul 10, 2020	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jul 18, 2023	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]. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 2006	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 14, 2023	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) -

Tuberous sclerosis syndrome Pathogenic:1 Other:1

not provided, no classification provided	curation	Tuberous sclerosis database (TSC2)	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 18, 2023	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. -

Lymphangiomyomatosis;C1846385:Isolated focal cortical dysplasia type II;C1860707:Tuberous sclerosis 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 09, 2021

- -

TSC2-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 11, 2023

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. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 05, 2023

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
Cadd	Pathogenic	32
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.96	D;.;.;.;.;.;.;.;.;.;.;.;D;.;D
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.7	M;.;.;.;M;M;.;.;.;M;.;M;.;.;.
MutationTaster	Benign	1.0	A;A;A;A;A;A;A
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-3.6	D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
Sift4G	Uncertain	0.0090	D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
Polyphen		1.0	D;.;.;.;D;D;.;.;D;D;.;.;.;.;.
Vest4		0.97
MutPred		0.89		Loss of MoRF binding (P = 0.0284);Loss of MoRF binding (P = 0.0284);Loss of MoRF binding (P = 0.0284);.;Loss of MoRF binding (P = 0.0284);Loss of MoRF binding (P = 0.0284);Loss of MoRF binding (P = 0.0284);Loss of MoRF binding (P = 0.0284);.;Loss of MoRF binding (P = 0.0284);Loss of MoRF binding (P = 0.0284);Loss of MoRF binding (P = 0.0284);Loss of MoRF binding (P = 0.0284);Loss of MoRF binding (P = 0.0284);.;
MVP		1.0
ClinPred		1.0	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.90
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs45517259; hg19: chr16-2126143; COSMIC: COSV54766635; COSMIC: COSV54766635;