rs28934872

Variant names:

• chr16-2070571-G-A
• rs28934872
• NM_000548.5:c.1832G>A
• TSC2 p.Arg611Gln

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PS3 PM1 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 (★★). ClinVar reports functional evidence for this variant: "SCV000544351: Experimental studies have shown that this missense change affects TSC2 function (PMID:11741832, 15483652, 18854862, 21309039, 26703369)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R611W) has been classified as 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:19 O:3
• Conservation: PhyloP100: 9.92
• Publications: 48 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: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Genomics England PanelApp
• 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 22 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000544351: Experimental studies have shown that this missense change affects TSC2 function (PMID: 11741832, 15483652, 18854862, 21309039, 26703369).; SCV000840073: 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).; SCV006557081: "In support of this prediction, functional studies demonstrate that this variant inhibits tuberin phosphorylation and prevents the formation of the tuberin‚Äìhamartin complex in multiple in vitro studies (Nellist M et al., PMID:11741832; Nellist M et al., PMID: 15483652; Nellist M et al., PMID: 15963462)."; SCV000491001: Functional studies indicate that R611Q disrupts the TSC1-TSC2 complex (Nellist et al., 2001; Nellist et al., 2005; Hoogeveen-Westerveld et al., 2011);; SCV003799245: Functional studies indicate the variant disrupts the interaction with hamartin and inhibits phosphorylation (Hoogeveen-Westerveld 2011, Nellist 2005). PMID: 21309039. PMID: 15483652.; SCV003802810: 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).; SCV000579587: 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).; SCV000899051: "in vitro functional studies further support an impact to the protein (Nellist 2001 PMID:11741832, Nellist 2005 PMID:15483652)."
• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 11 benign, 35 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-T is described in ClinVar as Pathogenic. ClinVar VariationId is 49643.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 12397.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000548.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSC2	NM_000548.5	MANE Select	c.1832G>A	p.Arg611Gln	missense	Exon 17 of 42	NP_000539.2	P49815-1
	TSC2	NM_001406663.1		c.1832G>A	p.Arg611Gln	missense	Exon 17 of 42	NP_001393592.1	A0A2R8Y6C9
	TSC2	NM_001114382.3		c.1832G>A	p.Arg611Gln	missense	Exon 17 of 41	NP_001107854.1	P49815-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSC2	ENST00000219476.9	TSL:5 MANE Select	c.1832G>A	p.Arg611Gln	missense	Exon 17 of 42	ENSP00000219476.3	P49815-1
	TSC2	ENST00000350773.9	TSL:1	c.1832G>A	p.Arg611Gln	missense	Exon 17 of 41	ENSP00000344383.4	P49815-4
	TSC2	ENST00000401874.7	TSL:1	c.1832G>A	p.Arg611Gln	missense	Exon 17 of 40	ENSP00000384468.2	P49815-5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

Alfa AF: 0.00000997 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
10	-	-	Tuberous sclerosis 2 (11)
5	-	-	not provided (5)
2	-	-	Lymphangiomyomatosis;C1846385:Isolated focal cortical dysplasia type II;C1860707:Tuberous sclerosis 2 (2)
1	-	-	Hereditary cancer-predisposing syndrome (1)
1	-	-	Lymphangiomyomatosis (2)
-	-	-	Tuberous sclerosis syndrome (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.58	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Pathogenic	2.9	M
PhyloP100		9.9
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-3.5	D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.012	D
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.78
gMVP		0.88
Mutation Taster		=0/100	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs28934872;

hg19: chr16-2120572;

COSMIC: COSV54758646;