16-2087897-C-T

Position:

• chr16-2087897-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The NM_000548.5(TSC2):​c.5024C>T​(p.Pro1675Leu) 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. 13/20 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1675Q) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TSC2 NM_000548.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:15 U:1 O:2
• Conservation: PhyloP100: 7.84

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 11 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-2087897-C-A is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• PP5: Variant 16-2087897-C-T is Pathogenic according to our data. Variant chr16-2087897-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 12393.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=13, not_provided=2}. Variant chr16-2087897-C-T is described in Lovd as [Pathogenic]. Variant chr16-2087897-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSC2	NM_000548.5	c.5024C>T	p.Pro1675Leu	missense_variant	39/42	ENST00000219476.9	NP_000539.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9	c.5024C>T	p.Pro1675Leu	missense_variant	39/42	5	NM_000548.5	ENSP00000219476.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:15 Uncertain:1 Other:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Tuberous sclerosis 2 Pathogenic:7 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 02, 2023	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1675 of the TSC2 protein (p.Pro1675Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with tuberous sclerosis complex (TSC) (PMID: 9302281, 9463313, 10570911, 11112665, 11520734, 12111193, 15024740, 21520333, 22867869). In at least one individual the variant was observed to be de novo. This variant is also known as 5042C>T and P1657L. ClinVar contains an entry for this variant (Variation ID: 12393). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects TSC2 function (PMID: 11290735, 22903760). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 14, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Division of Genomic Medicine, Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University	Jul 19, 2022	According to ACMG GL 2015, well-established in vitro functional studies supportive of a damaging effect of this variant (PS3), located in the GAP domain (PM1), absent from controls (PM2), assumed de novo (PM6). Multiple lines of computational evidence support a deleterious effect (PP3), and detected in the patient with clinically definitive tuberous sclerosis complex (PP4) and also reported as pathogenic in LOVD database (PP5). -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Mar 22, 2022	The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 9302281, 11520734, 12111193). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 22903760, 11290735). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.965>=0.6, 3CNET: 0.939>=0.75). It is not observed in the gnomAD v2.1.1 dataset. A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000535873). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 1997	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Mar 01, 2021	The TSC2 c.5024C>T variant is classified as a PATHOGENIC variant (PS3, PS4, PP3, PP4, PP5) The variant is a single nucleotide change from a cytosine to a thymine at position 5024 which is predicted to change the proline at position 1675 in the protein to leucine. The variant is in exon 39 and is located in RAP GTPases activating protein domain of the TSC2 gene. Furthermore, functional studies have shown that this variant decreases TSC2 protein expression levels, disrupts TSC2 phosphorylation, and prevents proper TSC2 protein binding with TSC1 (PMID: 11290735, 22903760) (PS3). The variant is considered as a recurrent change in the TSC2 gene, and has been reported many times in individuals with Tuberous sclerosis in the heterozygous state (PMID:9302281). The variant is in dbSNP (rs45483392) but is absent from population databases (PS4). The variant has been reported in ClinVar (Variation ID: 12393) and HGMD (Accession #: CM971532) as pathogenic (PP5). Computational predictions support a deleterious effect on the gene or gene product (PP3). The phenotype of this patient is highly specific for the TSC2 gene (PP4). -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Apr 04, 2024	- -

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 21, 2023	This variant has been identified in multiple unrelated individuals with clinical features associated with this gene, including both familial and de novo cases. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 11290735, 22903760) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	TSC2: PS2:Very Strong, PM2, PS4:Moderate, PP3, PS3:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 18, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 05, 2021	Functional studies indicate that P1675L is damaging to the protein (Hoogeveen-Westerveld et al., 2013; Aicher et al., 2001); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 12205112, 28065512, 32211034, 22903760, 11290735, 9302281, 23504366, 15024740, 12136241, 11112665, 25782670, 15121797, 11829138, 22867869, 10205261, 12111193, 27406250, 29801666, 31505689, 32313033) -

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

Pathogenic, criteria provided, single submitter	clinical testing	Juno Genomics, Hangzhou Juno Genomics, Inc	-	PM2_Supporting+PS4+PS2+PM5_Supporting+PS3_Moderate+PP3+PP4 -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Sep 28, 2021	- -

TSC2-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 01, 2024

The TSC2 c.5024C>T variant is predicted to result in the amino acid substitution p.Pro1675Leu. This variant has been reported as causative for tuberous sclerosis, and was found to be de novo in at least one patient (Maheshwar et al. 1997. PubMed ID: 9302281; Dabora et al. 2001. PubMed ID: 11112665; Aicher et al. 2001. PubMed ID: 11290735; Hoogeveen-Westerveld et al. 2013. PubMed ID: 22903760). A functional study showed that this variant affected phosphorylation and reduced interaction with hamartin (Aicher et al. 2001. PubMed ID: 11290735). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 08, 2023

The p.P1675L pathogenic mutation (also known as c.5024C>T), located in coding exon 38 of the TSC2 gene, results from a C to T substitution at nucleotide position 5024. The proline at codon 1675 is replaced by leucine, an amino acid with similar properties. This alteration has been found in multiple individuals who met diagnostic criteria for tuberous sclerosis complex (Ambry internal data; Feng JH et al. Hum. Mutat., 2004 Apr;23:397; Maheshwar MM et al. Hum. Mol. Genet.,1997 Oct;6:1991-6). In addition, in functional studies of the alteration, it was found that the TSC2 signal was significantly reduced compared to the wild-typed TSC1-TSC2 control (Hoogeveen-Westerveld M et al. Hum. Mutat., 2013 Jan;34:167-75). Lastly, further functional studies of this alteration demonstratedreduced phosphorylation and impaired interaction with hamartin (Aicher LD et al. J. Biol. Chem., 2001 Jun;276:21017-21). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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)

-

- -

Lymphangiomyomatosis Other:1

not provided, no classification provided

curation

Tuberous sclerosis database (TSC2)

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.98	D;.;.;.;.;.;.;.;.;.;.;.;D;.;D
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.86	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.0	M;.;.;.;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-8.8	D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0010	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		0.92
MutPred		0.89		Gain of sheet (P = 0.0085);.;.;.;.;.;.;.;.;.;.;.;.;.;.;
MVP		0.98
ClinPred		1.0	D
GERP RS		4.6
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.0
Varity_R		0.92
gMVP		0.84

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs45483392; hg19: chr16-2137898; COSMIC: COSV51927085; COSMIC: COSV51927085;