rs781371665

Variant names:

• chr9-132902616-G-A
• rs781371665
• NM_000368.5:c.2380C>T

Your query was ambiguous. Multiple possible variants found:

• chr9-132902616-G-A
• chr9-132902616-G-C
• chr9-132902616-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000368.5(TSC1):​c.2380C>T​(p.Gln794*) variant causes a stop gained 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 (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TSC1 NM_000368.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.48

Genes affected

TSC1 (HGNC:12362): (TSC complex subunit 1) This gene is a tumor suppressor gene that encodes the growth inhibitory protein hamartin. The encoded protein interacts with and stabilizes the GTPase activating protein tuberin. This hamartin-tuberin complex negatively regulates mammalian target of rapamycin complex 1 (mTORC1) signaling which is a major regulator of anabolic cell growth. This protein also functions as a co-chaperone for Hsp90 that inhibits its ATPase activity. This protein functions as a facilitator of Hsp90-mediated folding of kinase and non-kinase clients, including TSC2 and thereby preventing their ubiquitination and proteasomal degradation. 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.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-132902616-G-A is Pathogenic according to our data. Variant chr9-132902616-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 489349.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132902616-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC1	NM_000368.5	c.2380C>T	p.Gln794*	stop_gained	Exon 18 of 23	ENST00000298552.9	NP_000359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC1	ENST00000298552.9	c.2380C>T	p.Gln794*	stop_gained	Exon 18 of 23	1	NM_000368.5	ENSP00000298552.3
TSC1	ENST00000490179.4	c.2380C>T	p.Gln794*	stop_gained	Exon 19 of 24	3		ENSP00000495533.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Jan 10, 2018

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Q794X nonsense variant in the TSC1 gene has been reported previously in multiple unrelatedindividuals with a clinical diagnosis of tuberous sclerosis complex, including two individuals with denovo variants (Pompili et al., 2009; TSC1 LOVD). This pathogenic variant is predicted to cause lossof normal protein function either through protein truncation or nonsense-mediated mRNA decay.Furthermore, the Q794X variant is not observed in large population cohorts (Lek et al., 2016). Therefore, the presence of Q794X is consistent with the diagnosis of TSC in this individual. -

Jul 22, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The TSC1 c.2380C>T, p.Gln794Ter variant (rs781371665) is reported in the literature in several individuals with a diagnosis of tuberous sclerosis (Jiang 2021, Peron 2018, Pompili 2009). This variant is also reported in ClinVar (Variation ID: 489349), but is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Variants that introduce premature termination codons in TSC1 are responsible for almost all TSC1 associated tuberous sclerosis cases (Curatolo 2015). Based on available information, this variant is considered to be pathogenic. References: Curatolo P et al. Genotype/Phenotype Correlations in Tuberous Sclerosis Complex. Semin Pediatr Neurol. 2015 Dec;22(4):259-73. PMID: 26706013. Jiang T et al. Application of Trio-Whole Exome Sequencing in Genetic Diagnosis and Therapy in Chinese Children With Epilepsy. Front Mol Neurosci. 2021 Aug 19;14:699574. PMID: 34489640. Peron A et al. Deep phenotyping of patients with Tuberous Sclerosis Complex and no mutation identified in TSC1 and TSC2. Eur J Med Genet. 2018 Jul;61(7):403-410. PMID: 29432982. Pompili G et al. Magnetic resonance imaging of renal involvement in genetically studied patients with tuberous sclerosis complex. Eur J Radiol. 2009 Nov;72(2):335-41. PMID: 18835118. -

Tuberous sclerosis 1 Pathogenic:1

Mar 29, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. This variant has been observed in individual(s) with tuberous sclerosis complex (PMID: 29432982, 10533069, 28065512, 32313033). ClinVar contains an entry for this variant (Variation ID: 489349). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Gln794*) in the TSC1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TSC1 are known to be pathogenic (PMID: 10227394, 17304050). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	44
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.98	D
Vest4		0.87
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs781371665; hg19: chr9-135778003; COSMIC: COSV53768589; COSMIC: COSV53768589;