16-2070532-A-G

Position:

• chr16-2070532-A-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PM5 PP3_Strong PP5_Moderate

The NM_000548.5(TSC2):​c.1793A>G​(p.Tyr598Cys) 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 Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y598H) 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:2 O:1
• Conservation: PhyloP100: 9.25

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-2070531-T-C is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• PP5: Variant 16-2070532-A-G is Pathogenic according to our data. Variant chr16-2070532-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 50162.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2070532-A-G is described in Lovd as [Pathogenic]. Variant chr16-2070532-A-G is described in Lovd as [Likely_pathogenic]. Variant chr16-2070532-A-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSC2	NM_000548.5	c.1793A>G	p.Tyr598Cys	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.1793A>G	p.Tyr598Cys	missense_variant	17/42	5	NM_000548.5	ENSP00000219476.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tuberous sclerosis 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 12, 2022

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Tyr598 amino acid residue in TSC2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21309039, 21520333). 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: 22903760). 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) performed at Invitae indicates that this missense variant is expected to disrupt TSC2 protein function. ClinVar contains an entry for this variant (Variation ID: 50162). This missense change has been observed in individuals with tuberous sclerosis complex (TSC) (PMID: 21520333, 22903760; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 598 of the TSC2 protein (p.Tyr598Cys). -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 13, 2024

The p.Y598C pathogenic mutation (also known as c.1793A>G), located in coding exon 16 of the TSC2 gene, results from an A to G substitution at nucleotide position 1793. The tyrosine at codon 598 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant has been observed in multiple individuals with a personal and/or family history that is consistent with tuberous sclerosis complex (Ambry internal data; Milon V et al. Eur J Hum Genet, 2024 May; Kwiatkowski DJ et al. Eur J Hum Genet, 2015 Dec;23:1665-72). In one functional study, this alteration was found to have intermediate loss of the TSC1-TSC2 dependent inhibition of TORC1 (Hoogeveen-Westerveld M et al. Hum Mutat, 2013 Jan;34:167-75). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this variant 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	0.69
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	D;.;.;.;.;.;.;.;.;.;.;.;D;.;D
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Uncertain	2.9	M;.;.;.;M;M;.;.;.;M;.;M;.;.;.
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-7.9	D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
REVEL	Pathogenic	0.96
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		0.98
MutPred		0.82		Gain of methylation at K599 (P = 0.016);Gain of methylation at K599 (P = 0.016);Gain of methylation at K599 (P = 0.016);.;Gain of methylation at K599 (P = 0.016);Gain of methylation at K599 (P = 0.016);Gain of methylation at K599 (P = 0.016);Gain of methylation at K599 (P = 0.016);.;Gain of methylation at K599 (P = 0.016);Gain of methylation at K599 (P = 0.016);Gain of methylation at K599 (P = 0.016);Gain of methylation at K599 (P = 0.016);Gain of methylation at K599 (P = 0.016);.;
MVP		0.99
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.90
gMVP		0.78

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: rs45509791; hg19: chr16-2120533;