rs45517360

Variant names:

• chr16-2086202-G-A
• rs45517360
• NM_000548.5:c.4672G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-2086202-G-A
• chr16-2086202-G-C
• chr16-2086202-G-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_Very_Strong

The NM_000548.5(TSC2):​c.4672G>A​(p.Glu1558Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,460,318 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: TSC2 NM_000548.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8 O:1
• Conservation: PhyloP100: 7.92

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 14 ACMG points.

• PM1: In a domain Rap-GAP (size 227) in uniprot entity TSC2_HUMAN there are 284 pathogenic changes around while only 47 benign (86%) in NM_000548.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.895
• PP5: Variant 16-2086202-G-A is Pathogenic according to our data. Variant chr16-2086202-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 49794.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2086202-G-A is described in Lovd as [Pathogenic]. Variant chr16-2086202-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC2	NM_000548.5	c.4672G>A	p.Glu1558Lys	missense_variant	Exon 37 of 42	ENST00000219476.9	NP_000539.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9	c.4672G>A	p.Glu1558Lys	missense_variant	Exon 37 of 42	5	NM_000548.5	ENSP00000219476.3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1460318 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 726460

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tuberous sclerosis 2 Pathogenic:3

Dec 06, 2019

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 07, 2021

Genome-Nilou Lab

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1558 of the TSC2 protein (p.Glu1558Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of tuberous sclerosis complex (PMID: 11112665, 15798777, 16114042, 16417848, 32555378). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 49794). 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: 32555378). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:3

Jul 24, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The TSC2 c.4672G>A (p.Glu1558Lys) variant has been reported in the published literature in multiple TSC patients (PMIDs: 11112665 (2001), 16114042 (2005)) including one whose primary manifestation was multiple cardiac rhabdomyomas (PMID: 16417848 (2005)). Functional studies suggest that this variant is disruptive to TSC2 function (PMIDs: 32502382 (2020), 32555378 (2020)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic. -

Mar 13, 2025

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect: significantly increased mTORC1 activity as compared to wild type (PMID: 32555378); 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: 18307215, 15798777, 16417848, 11112665, 22750304, 19176517, 16114042, 18466115, 32555378) -

Apr 01, 2020

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Tuberous sclerosis syndrome Pathogenic:1 Other:1

-

Tuberous sclerosis database (TSC2)

Significance: not provided

Review Status: no classification provided

Collection Method: curation

- -

Jun 23, 2020

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Glu1558Lys variant in TSC2 has been reported in 1 de novo case (maternity and paternity confirmed) and 1 familial tuberous sclerosis case (Dabora 2001, Rendtorff 2005). It was also absent from large population studies. This variant has also been reported in ClinVar (Variation ID 49794). Computational prediction tools and conservation analysis suggest that the p.Glu1558Lys variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, the p.Glu1558Lys variant is likely pathogenic. ACMG/AMP Criteria applied: PS2; PM2; PP3; PS4_Supporting. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Dec 22, 2022

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.E1558K variant (also known as c.4672G>A), located in coding exon 36 of the TSC2 gene, results from a G to A substitution at nucleotide position 4672. The glutamic acid at codon 1558 is replaced by lysine, an amino acid with similar properties. This alteration has been identified in tuberous sclerosis complex (TSC) cohorts (Dabora SL et al. Am J Hum Genet, 2001 Jan;68:64-80; Rendtorff ND et al. Hum Mutat, 2005 Oct;26:374-83; Rosengren T et al. Sci Rep, 2020 Jun;10:9909). A proband with this variant was identified to have pediatric cardiac rhabdomyomas and periventricular calcifications, but was otherwise negative for skin lesions and neurological symptoms associated with TSC (Jówiak S et al. J Child Neurol, 2005 Dec;20:988-9). Protein functional studies have shown this variant results in an impairment of TSC2 function (Rosengren T et al. Sci Rep, 2020 Jun;10:9909). Other TSC2 missense alterations have been associated with reduced penetrance and milder phenotype, including variable expression within the same kindreds (Farach LS et al. Am J Med Genet A, 2017 Mar;173:771-775; Wentink M et al. Clin Genet, 2012 May;81:453-61). 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 majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.86	D;.;.;.;.;.;.;.;.;.;.;.;T;.;T
Eigen	Pathogenic	0.78
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.81	D
MetaRNN	Pathogenic	0.90	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.5	M;.;.;.;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-3.5	D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
Sift4G	Pathogenic	0.0	D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
Polyphen		1.0	D;.;.;.;D;D;.;.;D;D;.;.;.;.;.
Vest4		0.87
MutPred		0.64		Gain of ubiquitination at E1558 (P = 0.0104);.;.;.;.;.;.;.;.;.;.;.;.;.;.;
MVP		0.98
ClinPred		0.99	D
GERP RS		4.5
Varity_R		0.91
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs45517360; hg19: chr16-2136203; COSMIC: COSV99032343; COSMIC: COSV99032343;