16-2070570-C-T

Variant names:

• chr16-2070570-C-T
• rs45469298
• NM_000548.5:c.1831C>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000548.5(TSC2):​c.1831C>T​(p.Arg611Trp) variant causes a missense change involving the alteration of a non-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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R611G) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TSC2 NM_000548.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:10 O:1
• Conservation: PhyloP100: 2.17
• Publications: 41 publications found

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]

TSC2 Gene-Disease associations (from GenCC):

• tuberous sclerosis

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• tuberous sclerosis 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, Ambry Genetics
• lymphangioleiomyomatosis

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• tuberous sclerosis complex

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 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 11 benign, 33 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 chr16-2070570-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 49177.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant 16-2070570-C-T is Pathogenic according to our data. Variant chr16-2070570-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 49643.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC2	NM_000548.5	c.1831C>T	p.Arg611Trp	missense_variant	Exon 17 of 42	ENST00000219476.9	NP_000539.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9	c.1831C>T	p.Arg611Trp	missense_variant	Exon 17 of 42	5	NM_000548.5	ENSP00000219476.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00 AC: 0 AN: 250146 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tuberous sclerosis 2 Pathogenic:6

Jul 10, 2020

Division of Genomic Medicine, Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 07, 2021

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 611 of the TSC2 protein (p.Arg611Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with tuberous sclerosis (PMID: 8824881, 10205261, 10735580, 12111193, 15595939, 17304050, 22867869, 26540169). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 49643). Invitae Evidence 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 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: 11741832, 15483652, 15963462). This variant disrupts the p.Arg611 amino acid residue in TSC2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9463313, 10205261, 15595939, 17304050). 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. -

May 22, 2024

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 35712104, 36232477, 10205261, 32313033, 32917966, 27859028]. Functional studies indicate this variant impacts protein function [PMID: 11741832, 15483652, 15963462]. This variant is expected to disrupt protein structure [Myriad internal data]. -

Apr 04, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 14, 2024

Clinical Genomics Laboratory, Washington University in St. Louis

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A TSC2: c.1831C>T (p.Arg611Trp) missense variant was identified at an allelic fraction consistent with somatic origin. This variant has been reported in multiple individuals affected with tuberous sclerosis syndrome, isolated focal cortical dysplasia type II and lymphangiomyomatosis with germline origin (Togi S et al., PMID: 36232477; Wang X et al., PMID: 35712104; Reyna-Fabián ME et al. PMID: 32313033; Tyburczy ME et al., PMID: 26540169; Au KS et al., PMID: 17304050; Nellist M et al., PMID: 15483652). This variant has been reported in the ClinVar database as pathogenic by multiple submitters (ClinVar ID:49643) and has been reported in a somatic state in four cases in the cancer database COSMIC (Genomic mutation ID: COSV54770134). Other variants at the same codon, (p.Arg611Gln and p.Arg611Gly), have been reported in individuals with tuberous sclerosis 2 (Rosengren T et al., PMID: 32555378; Hoogeveen-Westerveld M et al., PMID: 21309039; Au KS et al., PMID: 17304050). The TSC2: c.1831C>T (p.Arg611Trp) variant is absent from the general population (gnomAD v.4.1.0), indicating it is not a common variant. Computational predictors indicate that the variant is damaging, evidence that correlates with impact to TSC2 function. In support of this prediction, functional studies demonstrate that this variant inhibits tuberin phosphorylation and prevents formation of the tuberin–hamartin complex in multiple in vitro studies (Nellist M et al., PMID:11741832; Nellist M et al., PMID: 15483652; Nellist M et al., PMID: 15963462). Based on available information and an internally developed protocol informed by the ACMG/AMP guidelines for variant interpretation and gene-specific practices from the ClinGen Criteria Specification Registry (Leon-Quintero FZ et al., PMID: 39434542), the TSC2: c.1831C>T (p.Arg611Trp) variant is classified as pathogenic. -

not provided Pathogenic:2

Jul 11, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate this position is critical to the chaperone function of the tuberin protein, and substitutions at this position disrupt tuberin-hamartin complex formation (PMID: 11741832, 15483652); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 15595939, 15483652, 22867869, 21309039, 27859028, 29655203, 30712878, 32211034, 32313033, 30787465, 34540963, 32917966, 35712104, 36307859, 36232477, 34489640, 8824881, 11741832) -

May 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

-

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TSC2 NM_000548.4 exon 17 p.Arg611Trp (c.1831C>T): This variant has been well reported in the literature, described in several individuals with tuberous sclerosis, at least one of whom was reported to be de novo (Wilson 1996 PMID:8824881, Choy 1999 PMID:10735580, Jones 1999 PMID:10205261, Ali 2005 PMID:15595939, Au 2007 PMID:17304050, van Eeghen 2013 PMID:22867869, Tyburczy 2015 PMID:26540169). This variant is not present in large control databases. This variant is present in ClinVar, with several labs classifying this variant as pathogenic (Variation ID:49643). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In addition, functional studies also predict that this variant will impact the protein (Nellist 2001 PMID:11741832, Nellist 2005 PMID:15483652). Other variants at this same codon (p.Arg611Gln, p.Arg611Gly) have been reported in association with disease in the literature, supporting that this region has significance. In summary, this variant is classified as pathogenic -

Hereditary cancer-predisposing syndrome Pathogenic:1

Jun 27, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R611W pathogenic mutation (also known as c.1831C>T), located in coding exon 16 of the TSC2 gene, results from a C to T substitution at nucleotide position 1831. The arginine at codon 611 is replaced by tryptophan, an amino acid with dissimilar properties. This variant has been detected in multiple individuals meeting diagnostic criteria for tuberous sclerosis complex (TSC) (Wilson PJ, et al. Hum. Mol. Genet. 1996; 5(2):249-56; Choy YS, et al. Ann. Hum. Genet. 1999; 63(Pt 5):383-91; Langkau N, et al. Eur. J. Pediatr. 2002; 161(7):393-402; Ali M, et al. Acta Neurol. Scand. 2005; 111(1):54-63; Ambry internal data). In one functional study, authors showed that this variant inhibits tuberin-hamartin binding, tuberin chaperone function, S6 and S6K phosphorylation and the stimulation of rheb GTPase activity (Nellist M, et al. Eur. J. Hum. Genet. 2005; 13(1):59-68; Nellist M, et al. Hum. Mol. Genet. 2001). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation. -

Tuberous sclerosis syndrome Other:1

-

Tuberous sclerosis database (TSC2)

Significance: not provided

Review Status: no classification provided

Collection Method: curation

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.94	D;.;.;.;.;.;.;.;.;.;.;.;D;.;D
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.97	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.80	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Pathogenic	2.9	M;.;.;.;M;M;.;.;.;M;.;M;.;.;.
PhyloP100		2.2
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-7.3	D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
REVEL	Pathogenic	0.87
Sift	Pathogenic	0.0	D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
Sift4G	Pathogenic	0.0010	D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
Polyphen		1.0	D;.;.;.;D;D;.;.;D;D;.;.;.;.;.
Vest4		0.98
MutPred		0.97		Gain of helix (P = 0.1736);Gain of helix (P = 0.1736);Gain of helix (P = 0.1736);.;Gain of helix (P = 0.1736);Gain of helix (P = 0.1736);Gain of helix (P = 0.1736);Gain of helix (P = 0.1736);.;Gain of helix (P = 0.1736);Gain of helix (P = 0.1736);Gain of helix (P = 0.1736);Gain of helix (P = 0.1736);Gain of helix (P = 0.1736);.;
MVP		0.99
ClinPred		0.99	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.90
gMVP		0.91
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs45469298; hg19: chr16-2120571; COSMIC: COSV54770134; COSMIC: COSV54770134;