rs118203597

Positions:

• chr9-132905672-CTG-C

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.1904_1905delCA​(p.Thr635fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:12 O:2
• Conservation: PhyloP100: 1.36

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]

TSC1 (HGNC:):

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 9-132905672-CTG-C is Pathogenic according to our data. Variant chr9-132905672-CTG-C is described in ClinVar as [Pathogenic]. Clinvar id is 5100.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132905672-CTG-C is described in Lovd as [Pathogenic]. Variant chr9-132905672-CTG-C is described in Lovd as [Pathogenic]. Variant chr9-132905672-CTG-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSC1	NM_000368.5	c.1904_1905delCA	p.Thr635fs	frameshift_variant	15/23	ENST00000298552.9	NP_000359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSC1	ENST00000298552.9	c.1904_1905delCA	p.Thr635fs	frameshift_variant	15/23	1	NM_000368.5	ENSP00000298552.3
TSC1	ENST00000490179.4	c.1904_1905delCA	p.Thr635fs	frameshift_variant	16/24	3		ENSP00000495533.2

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tuberous sclerosis 1 Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 05, 2023	This sequence change creates a premature translational stop signal (p.Thr635Argfs*52) 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). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 5100). This variant is also known as 2122delAC. This premature translational stop signal has been observed in individual(s) with tuberous sclerosis complex (TSC) (PMID: 9242607, 10053179, 21520333). This variant is not present in population databases (gnomAD no frequency). -
Pathogenic, criteria provided, single submitter	research	Molecular Biology Laboratory, Fundació Puigvert	Feb 01, 2020	- -
Pathogenic, no assertion criteria provided	clinical testing	Division of Genomic Medicine, Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University	Jun 09, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Consultorio y Laboratorio de Neurogenética, Hospital JM Ramos Mejia	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Sep 06, 2022	Criteria applied: PVS1,PS4,PM2_SUP -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Feb 21, 2024	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 04, 1999	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -

Tuberous sclerosis syndrome Pathogenic:1 Other:2

not provided, no classification provided	curation	Tuberous sclerosis database (TSC1)	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Aug 29, 2023	- -
not provided, no classification provided	curation	Tuberous sclerosis database (TSC1)	-	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Athena Diagnostics

Nov 22, 2017

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 26, 2023

The c.1904_1905delCA pathogenic mutation, located in coding exon 13 of the TSC1 gene, results from a deletion of two nucleotides at nucleotide positions 1904 to 1905, causing a translational frameshift with a predicted alternate stop codon (p.T635Rfs*52). This alteration has been observed in multiple individuals with a personal history that is consistent with TSC1-related disease (Au KS et al. Genet Med, 2007 Feb;9:88-100; Ding Y et al. Front Genet, 2020 Mar;11:204; Dong X et al. J Med Genet, 2020 Aug;57:558-566; Meng Y et al. J Hum Genet, 2021 Mar;66:227-236). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

TSC1-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Swedish National ChiCaP Initative, Genomic Medicine Sweden

May 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs118203597; hg19: chr9-135781059;