rs45516293

chr16-2084965-A-Cchr16-2084965-A-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000548.5(TSC2):c.4508A>C(p.Gln1503Pro) 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. Q1503H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 34)
• Consequence: TSC2 NM_000548.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9 O:2
• Conservation: PhyloP100: 7.36

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 18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 17 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 chr16-2084966-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 49498.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.952
• PP5: Variant 16-2084965-A-C is Pathogenic according to our data. Variant chr16-2084965-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 12401.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2084965-A-C is described in Lovd as [Pathogenic]. Variant chr16-2084965-A-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSC2	NM_000548.5	c.4508A>C	p.Gln1503Pro	missense_variant	35/42	ENST00000219476.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSC2	ENST00000219476.9	c.4508A>C	p.Gln1503Pro	missense_variant	35/42	5	NM_000548.5

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 34

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tuberous sclerosis 2 Pathogenic:4 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 2001	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jan 31, 2023	This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 11403047]. Functional studies indicate this variant impacts protein function [PMID: 21332470, 22903760]. This variant is expected to disrupt protein structure [internal Myriad data]. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Mar 07, 2023	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. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects TSC2 function (PMID: 21332470, 22903760). ClinVar contains an entry for this variant (Variation ID: 12401). This missense change has been observed in individual(s) with mild manifestations of tuberous sclerosis complex (TSC) (PMID: 11403047). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 1503 of the TSC2 protein (p.Gln1503Pro). -

Tuberous sclerosis syndrome Pathogenic:2 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 28, 2017	Variant summary: The TSC2 c.4508A>C (p.Gln1503Pro) variant involves the alteration of a conserved nucleotide that lies within the Rap GTPase activating protein domain (InterPro). 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant is absent in 120242 control chromosomes (ExAC and publication controls). The variant was identified in two families from the same geographical area with multiple affected individuals in each family. While the physical features typical of tuberous sclerosis were mild, affected individuals had significant neuropsychiatric symptoms including pervasive developmental disorder and autism. The variant cosegregated with disease completely in 14 affected and 9 unaffected individuals (Khare_JMG_2001). A functional study revealed the variant was unable to inhibit S6K phosphorylation in cultured cells (Wentink_Clin Genet_2011). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 03, 2019	The p.Gln1503Pro variant in TSC2 has been reported in at least 2 individuals with features of tuberous sclerosis 2 syndrome (with neurodevelopmental disorder) and segregated with disease in 14 affected individuals from 2 families (Khare 2001). This variant has also been reported in ClinVar (Variation ID 12401) and was absent from large population studies. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In vitro functional studies support an impact on protein function (Hoogeveen-Westerveld M 2013). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant Tuberous sclerosis 2 syndrome. ACMG/AMP Criteria applied: PS4_Supporting, PP1_Strong, PM2, PS3_Supporting, PP3. -
not provided, no classification provided	curation	Tuberous sclerosis database (TSC2)	-	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 02, 2023

Reported previously as a heterozygous likely pathogenic variant in a patient with epilepsy; however, no further clinical or segregation information was provided (Truty et al., 2019); Published functional studies demonstrate a damaging effect showing that the variant disrupts the function of the TSC1-TSC2 complex (Wentink et al., 2012; Hoogeveen-Westerveld et al., 2013); 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: 19028034, 21332470, 23389244, 11403047, 17120248, 28492532, 30255984, 31440721, 22903760, 27535533, 17304050) -

Isolated focal cortical dysplasia type II Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

May 02, 2023

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 12, 2016

The p.Q1503P pathogenic mutation (also known as c.4508A>C), located in coding exon 34 of the TSC2 gene, results from an A to C substitution at nucleotide position 4508. The glutamine at codon 1503 is replaced by proline, an amino acid with similar properties. This pathogenic mutation was identified in two unrelated four-generation families with tuberous sclerosis complex; it co-segregated with the disease in those families (Khare L et al. J. Med. Genet., 2001 May;38:347-9). Furthermore, in vitro assay of the Q1503P mutant protein revealed that this mutation significantly increases T389-phosphorylated S6 kinase, thereby preventing the TSC-TSC2-dependent inhibition of the target of rapamycin complex 1 (TORC1) activity (Wentink M et al. Clin. Genet., 2012 May;81:453-61; Hoogeveen-Westerveld M et al. Hum. Mutat., 2013 Jan;34:167-75). Based on the available evidence, this variant is classified as a pathogenic mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.46
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D;.;.;.;.;.;.;.;.;.;.;.;D;.;D
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.3	M;.;.;.;.;.;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	A;A;A;A;A;A;A
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-5.0	D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
REVEL	Pathogenic	0.97
Sift	Uncertain	0.0020	D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
Sift4G	Uncertain	0.0060	D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
Polyphen		0.99	D;.;.;.;D;D;.;.;D;D;.;.;.;.;.
Vest4		0.82
MutPred		0.74		Loss of catalytic residue at Q1503 (P = 0.0039);.;.;.;.;.;.;Loss of catalytic residue at Q1503 (P = 0.0039);.;.;.;.;.;.;.;
MVP		0.99
ClinPred		0.99	D
GERP RS		5.0
Varity_R		0.98
gMVP		0.97

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: rs45516293; hg19: chr16-2134966;