rs28934872

Positions:

• chr16-2070571-G-A

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.1832G>A​(p.Arg611Gln) 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. R611G) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TSC2 NM_000548.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:16 O:3
• 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 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, 0.99
• PP5: Variant 16-2070571-G-A is Pathogenic according to our data. Variant chr16-2070571-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 12397.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2070571-G-A is described in Lovd as [Pathogenic]. Variant chr16-2070571-G-A is described in Lovd as [Pathogenic]. Variant chr16-2070571-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSC2	NM_000548.5	c.1832G>A	p.Arg611Gln	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.1832G>A	p.Arg611Gln	missense_variant	17/42	5	NM_000548.5	ENSP00000219476

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

Alfa AF: 0.00152 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:16 Other:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tuberous sclerosis 2 Pathogenic:7 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -
Likely pathogenic, criteria provided, single submitter	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 25, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 20, 2023	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 611 of the TSC2 protein (p.Arg611Gln). 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: 9463313, 10205261, 15595939, 17304050). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 12397). 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: 11741832, 15483652, 18854862, 21309039, 26703369). 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	- -
Pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Dec 04, 2017	This c.1832G>A (p.Arg611Gln) variant in the TSC2 gene has been reported in multiple unrelated individuals with Tuberous Sclerosis (PMID: 9463313, 10570911, 15595939). Functional studies have shown that the p.Arg611Gln mutant tuberin protein (encoded by the TSC2 gene) has decreased interaction with its binding partner, hamartin, and is unable to inhibit the mTOR pathway properly (PMID: 11741832, 15483652, 15963462, 18302728, 18308511, 21309039). The c.1832G>A variant in TSC2 is not present in the general population. This c.1832G>A (p.Arg611Gln) variant in the TSC2 gene is classified as pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 23, 2000	- -
not provided, no classification provided	literature only	SN ONGC Dept of Genetics and Molecular biology Vision Research Foundation	-	- -

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	TSC2: PM6:Strong, PM2, PM5, PS3:Moderate, PS4:Moderate, PP4 -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 14, 2019	Not found in the total gnomAD dataset, and the data is high quality. This variant is statistically more frequent in affected individuals than in the general population and/or healthy controls. Predicted to have a damaging effect on the protein. Assessment of experimental evidence suggests this variant results in abnormal protein function. One de novo case with parental identity confirmed plus 1 unconfirmed case. -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 18, 2022	The TSC2 c.1832G>A; p.Arg611Gln variant (rs28934872) is described in the literature in several individuals with a clinical diagnosis of tuberous sclerosis complex, including the variant occurring de novo in at least three individuals (Babol-Pokora 2021, Reyna-Fabian 2020, Suspitsin 2018). The variant is listed as pathogenic by several sources in the ClinVar database (Variation ID: 12397) and is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. The arginine at codon 611 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.893). Functional studies indicate the variant disrupts the interaction with hamartin and inhibits phosphorylation (Hoogeveen-Westerveld 2011, Nellist 2005). Based on available information, this variant is classified as pathogenic. References: Babol-Pokora K et al. A multistep approach to the genotype-phenotype analysis of Polish patients with tuberous sclerosis complex. Eur J Med Genet. 2021 Oct;64(10):104309. PMID: 34403804. 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. PMID: 21309039. Nellist M et al. Distinct effects of single amino-acid changes to tuberin on the function of the tuberin-hamartin complex. Eur J Hum Genet. 2005 Jan;13(1):59-68. PMID: 15483652. Reyna-Fabian ME et al. First comprehensive TSC1/TSC2 mutational analysis in Mexican patients with Tuberous Sclerosis Complex reveals numerous novel pathogenic variants. Sci Rep. 2020 Apr 20;10(1):6589. PMID: 32313033. Suspitsin EN et al. Pattern of TSC1 and TSC2 germline mutations in Russian patients with tuberous sclerosis. J Hum Genet. 2018 May;63(5):597-604. PMID: 29476190. -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Sep 15, 2022	The TSC2 c.1832G>A (p.Arg611Gln) missense variant results in the substitution of arginine at amino acid position 611 with glutamine. Across a selection of available literature, the c.1832G>A variant has been reported in at least 17 individuals with tuberous sclerosis complex, with several described as occurring de novo (PMID: 9463313; PMID: 15595939; PMID: 22867869; PMID: 32555378). Another variant at the same amino acid position, c.1831C>T (p.Arg611Trp), has been reported in a heterozygous state in at least six individuals with tuberous sclerosis complex (PMID: 15595939; PMID: 22867869). The c.1832G>A variant is not found in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. Functional analysis using mass spectrometry and coimmunoprecipitation determined the c.1832G>A variant is associated with loss of phosphorylation and is inactivated due to protein mis-folding (PMID: 15963462). This variant was identified in a de novo state. Based on the available evidence, the c.1832G>A (p.Arg611Gln) variant is classified as pathogenic for tuberous sclerosis complex. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 09, 2021	Functional studies indicate that R611Q disrupts the TSC1-TSC2 complex (Nellist et al., 2001; Nellist et al., 2005; Hoogeveen-Westerveld et al., 2011); Not observed at significant frequency in large population cohorts (Lek et al., 2016); 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: 31447099, 27542907, 22867869, 15483652, 15798777, 11741832, 27216612, 26703369, 27406250, 29632054, 29129521, 29308833, 29476190, 16032769, 30293248, 31083211, 32555378, 31799751, 32340510, 32313033, 18466115, 30787465, 9463313, 32211034, 21309039) -

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

Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Mar 30, 2021	TSC2 NM_000548.4 exon 17 p.Arg611Gln (c.1832G>A): This variant has been reported in the literature in several individuals with tuberous sclerosis, at least one of whom was determined to be de novo (Au 1998 PMID:9463313, van Eeghen 2013 PMID:22867869, Overwater 2016 PMID:27406250). 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:12397). Evolutionary conservation and computational predictive tools predict that this variant may impact the protein. Additionally, in vitro functional studies further support an impact to the protein (Nellist 2001 PMID:11741832, Nellist 2005 PMID:15483652). Furthermore, another variant at this same codon (p.Arg611Trp) has been reported in the literature in association with disease and has been seen by our lab in an individual with tuberous sclerosis, further supporting that this region has significance. In summary, this variant is classified as pathogenic based on the data above. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 02, 2022	- -

Lymphangiomyomatosis Pathogenic:1 Other:1

not provided, no classification provided	curation	Tuberous sclerosis database (TSC2)	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 23, 2000	- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 08, 2023

The p.R611Q pathogenic mutation (also known as c.1832G>A), located in coding exon 16 of the TSC2 gene, results from a G to A substitution at nucleotide position 1832. The arginine at codon 611 is replaced by glutamine, an amino acid with some highly similar properties. This pathogenic mutation has been shown to inactivate the tuberin-hamartin complex, disrupt the ability of the tuberin protein to chaperone the hamartin protein throughout the cell, disrupt the phosphorylation of the tuberin protein and several downstream target proteins, and to cause the loss of GTPase activity stimulation (Nellist M et al. Hum. Mol. Genet. 2001 Dec; 10(25):2889-98; Nellist M et al. Eur. J. Hum. Genet. 2005 Jan; 13(1):59-68). This pathogenic mutation has been reported as a de novo finding in unrelated individuals with tuberous sclerosis complex (TSC) (Au KS et al. Am. J. Hum. Genet. 1998 Feb; 62(2):286-94), and has also been reported in multiple individuals diagnosed with TSC and infantile spasms (van Eeghen AM et al. Epilepsy Res. 2013 Jan; 103(1):83-7). Another alteration at this codon, p.R611W (c.1831C>T), has also been classified as a pathogenic mutation in the literature (Nellist M et al. Hum. Mol. Genet. 2001 Dec; 10(25):2889-98; Nellist M et al. Eur. J. Hum. Genet. 2005 Jan; 13(1):59-68). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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 supporting evidence, this alteration 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	0.94
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.93	D;.;.;.;.;.;.;.;.;.;.;.;D;.;D
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.58	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	A;A;A;A;A;A;A
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-3.5	D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0030	D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
Sift4G	Uncertain	0.012	D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
Polyphen		1.0	D;.;.;.;D;D;.;.;D;D;.;.;.;.;.
Vest4		0.98
MutPred		0.96		Loss of methylation at R611 (P = 0.2221);Loss of methylation at R611 (P = 0.2221);Loss of methylation at R611 (P = 0.2221);.;Loss of methylation at R611 (P = 0.2221);Loss of methylation at R611 (P = 0.2221);Loss of methylation at R611 (P = 0.2221);Loss of methylation at R611 (P = 0.2221);.;Loss of methylation at R611 (P = 0.2221);Loss of methylation at R611 (P = 0.2221);Loss of methylation at R611 (P = 0.2221);Loss of methylation at R611 (P = 0.2221);Loss of methylation at R611 (P = 0.2221);.;
MVP		0.99
ClinPred		0.99	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.78
gMVP		0.88

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: rs28934872; hg19: chr16-2120572; COSMIC: COSV54758646; COSMIC: COSV54758646;