16-2070570-C-T

Position:

• chr16-2070570-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. 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 Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TSC2 NM_000548.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9 O:1
• Conservation: PhyloP100: 2.17

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 16 ACMG points.

• 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 Lovd as [Likely_pathogenic].
• 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 id is 49643.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2070570-C-T is described in Lovd as [Pathogenic]. Variant chr16-2070570-C-T is described in Lovd as [Pathogenic]. Variant chr16-2070570-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSC2	NM_000548.5	c.1831C>T	p.Arg611Trp	missense_variant	17/42	ENST00000219476.9	NP_000539.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9	c.1831C>T	p.Arg611Trp	missense_variant	17/42	5	NM_000548.5	ENSP00000219476

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tuberous sclerosis 2 Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	May 22, 2024	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]. -
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	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Apr 04, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 17, 2023	For these reasons, this variant has been classified as Pathogenic. 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. Experimental studies have shown that this missense change affects TSC2 function (PMID: 11741832, 15483652, 15963462). 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. ClinVar contains an entry for this variant (Variation ID: 49643). 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. This variant is not present in population databases (gnomAD no frequency). 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). -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 09, 2020	Observed in multiple unrelated patients from different ethnic backgrounds with tuberous sclerosis in published literature and well-curated databases and not observed in controls (Wilson et al., 1996; TSC2 LOVD); 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 (Nellist et al., 2001; Nellist et al., 2005); Missense variants in nearby residues reported in the Human Gene Mutation Database in individuals with tuberous sclerosis (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 15595939, 15483652, 22867869, 11741832, 21309039, 8824881, 27859028, 29655203, 30712878, 32211034, 32313033) -

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

Pathogenic, criteria provided, single submitter

clinical testing

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

Oct 26, 2022

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

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 01, 2019

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 mutation has been detected in multiple individuals meeting diagnostic criteria for Tuberous sclerosis complex (TSC) (Ali M, et al. Acta Neurol. Scand. 2005; 111(1):54-63; Choy YS, et al. Ann. Hum. Genet. 1999; 63(Pt 5):383-91; Wilson PJ, et al. Hum. Mol. Genet. 1996; 5(2):249-56, Langkau N, et al. Eur. J. Pediatr. 2002; 161(7):393-402). In one functional study, authors showed that this mutation 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, p.R611W is interpreted as a disease-causing mutation. -

Tuberous sclerosis syndrome Other:1

not provided, no classification provided

curation

Tuberous sclerosis database (TSC2)

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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;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
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

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

Publications

LitVar

Other links and lift over

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