rs118203478

chr9-132911492-C-CAchr9-132911492-C-CAA

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.989_990insT(p.Ser331GlufsTer10) 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 (★★). Synonymous variant affecting the same amino acid position (i.e. L330L) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 31)
• Consequence: TSC1 NM_000368.5 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9 O:1
• Conservation: PhyloP100: 2.31

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 9-132911492-C-CA is Pathogenic according to our data. Variant chr9-132911492-C-CA is described in ClinVar as [Pathogenic]. Clinvar id is 49135.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSC1	NM_000368.5	c.989_990insT	p.Ser331GlufsTer10	frameshift_variant	10/23	ENST00000298552.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSC1	ENST00000298552.9	c.989_990insT	p.Ser331GlufsTer10	frameshift_variant	10/23	1	NM_000368.5	P4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9 Other:1

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	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 09, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 29, 2022	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Aug 05, 2023	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 49135). This variant is also known as c.990insT and c.1210insT. This premature translational stop signal has been observed in individual(s) with tuberous sclerosis complex (PMID: 10227394, 10570911, 23341583, 28968464). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ser331Glufs*10) 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). -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 22, 2022	Reported previously multiple times (sometimes using alternative nomenclature 1210insT) in association with TSC (van Slegtenhorst et al., 1999; Zhang et al., 1999; TSC1 LOVD).; 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 in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 15798777, 31855466, 29655203, 25782670, 10570911, 23341583, 28968464, 10227394) -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 15, 2019	PVS1, PS4_moderate, PM2, PP4 -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 17, 2019

The c.989dupT pathogenic mutation, located in coding exon 8 of the TSC1 gene, results from a duplication of T at nucleotide position 989, causing a translational frameshift with a predicted alternate stop codon. This mutation has been reported in multiple individuals who met clinical criteria for tuberous sclerosis complex (TSC); this alteration is also referred to as 1210insT, 989insT, and c.990insT in the literature (van Slegtenhorst M et al. J Med Genet. 1999; 36(4):285-9; Zhang H et al. J Hum Genet. 1999; 44(6):391-6; Dunet V et al. BMJ Case Rep. 2013; 2013; Rosset C et al. PLoS ONE. 2017 Oct;12:e0185713). 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. -

Cortical dysplasia;C1565489:Renal insufficiency;C1969144:Renal cortical cysts Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Oct 21, 2015

- -

Tuberous sclerosis syndrome Other:1

not provided, no classification provided

curation

Tuberous sclerosis database (TSC1)

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Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs118203478; hg19: chr9-135786879;