rs118203707

chr9-132900827-CTGTT-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000368.5(TSC1):c.2509_2512del(p.Asn837ValfsTer11) variant causes a frameshift change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. N837N) has been classified as Likely benign. 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:10 O:2
• Conservation: PhyloP100: 7.76

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 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 9-132900827-CTGTT-C is Pathogenic according to our data. Variant chr9-132900827-CTGTT-C is described in ClinVar as [Pathogenic]. Clinvar id is 48971.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132900827-CTGTT-C is described in Lovd as [Pathogenic]. Variant chr9-132900827-CTGTT-C is described in Lovd as [Pathogenic]. Variant chr9-132900827-CTGTT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSC1	NM_000368.5	c.2509_2512del	p.Asn837ValfsTer11	frameshift_variant	20/23	ENST00000298552.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSC1	ENST00000298552.9	c.2509_2512del	p.Asn837ValfsTer11	frameshift_variant	20/23	1	NM_000368.5	P4

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:10 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tuberous sclerosis 1 Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 19, 2023	This sequence change creates a premature translational stop signal (p.Asn837Valfs*11) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with tuberous sclerosis (PMID: 9924605, 29286531). This variant is also known as c.2729_2732delAAAC and c.2506_2509del. ClinVar contains an entry for this variant (Variation ID: 48971). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jan 10, 2023	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -
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	Athena Diagnostics	Jul 30, 2014	- -

not provided Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 30, 2023	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 14756965, 18032745, 15798777, 9924605, 17304050, 10227394, 10363127, 11112665, 31598950, 12015165, 29286531, 32211034) -

Tuberous sclerosis syndrome Other:2

not provided, no classification provided	curation	Tuberous sclerosis database (TSC1)	-	- -
not provided, no classification provided	curation	Tuberous sclerosis database (TSC1)	-	- -

Seizure;C0431718:Multiple renal cysts;C1968959:Cortical tubers Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Mar 27, 2014

- -

Lymphangiomyomatosis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 01, 2016

This variant was classified as: Pathogenic. -

Computational scores

Source: dbNSFP v4.3

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: rs118203707; hg19: chr9-135776214;