rs118203606

Positions:

• chr9-132905615-G-A
• chr9-132905615-G-C
• chr9-132905615-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.1963C>T​(p.Gln655Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.000000684 in 1,461,872 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TSC1 NM_000368.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4 O:1
• Conservation: PhyloP100: 5.60

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 9-132905615-G-A is Pathogenic according to our data. Variant chr9-132905615-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 48859.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132905615-G-A is described in Lovd as [Pathogenic]. Variant chr9-132905615-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSC1	NM_000368.5	c.1963C>T	p.Gln655Ter	stop_gained	15/23	ENST00000298552.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSC1	ENST00000298552.9	c.1963C>T	p.Gln655Ter	stop_gained	15/23	1	NM_000368.5	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461872 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727238

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 19, 2017	The p.Q655* pathogenic mutation (also known as c.1963C>T), located in coding exon 13 of the TSC1 gene, results from a C to T substitution at nucleotide position 1963. This changes the amino acid from a glutamine to a stop codon within coding exon 13. This alteration has been identified in a patient meeting diagnostic criteria for tuberous sclerosis complex (TSC) whose parents tested negative for this alteration (Niida Y et al. Hum. Mutat., 1999;14:412-22). In a different study, this alteration was identified as a familial mutation in an individual with a clinical diagnosis of TSC (Yamashita Y et al. Am. J. Med. Genet., 2000 Jan;90:123-6). The 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. -
Pathogenic, criteria provided, single submitter	research	Hauer Lab, Department Of Pediatric Oncology, Technical University Munich	-	ACMG/AMP, PVS1, PM2, PP5 -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Dec 16, 2014

p.Gln655Ter (CAG>TAG): c.1963 C>T in exon 15 of the TSC1 gene (NM_000368.4). The Q655X nonsense mutation in the TSC1 gene has been reported previously in multiple unrelated individuals with a clinical diagnosis of tuberous sclerosis (Niida et al., 1999; Yamashita et al., 2000; Sancak et al., 2005). This mutation is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The presence of Q655X is consistent with a diagnosis of tuberous sclerosis. The variant is found in TUBSC-EPIV2-1 panel(s). -

Tuberous sclerosis 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Sep 22, 2023

For these reasons, this variant has been classified as Pathogenic. This sequence change creates a premature translational stop signal (p.Gln655*) 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 complex (PMID: 10533067). This variant is also known as 2184C>T. ClinVar contains an entry for this variant (Variation ID: 48859). -

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

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.61	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	39
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	0.98	D
MutationTaster	Benign	1.0	A;A;A;D
Vest4		0.94
GERP RS		5.9
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: rs118203606; hg19: chr9-135781002;