rs118203595

chr9-132905686-GCTTT-G

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.1888_1891del(p.Lys630GlnfsTer22) variant causes a frameshift change. 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. K630K) 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:9 O:2
• Conservation: PhyloP100: 4.59

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 9-132905686-GCTTT-G is Pathogenic according to our data. Variant chr9-132905686-GCTTT-G is described in ClinVar as [Pathogenic]. Clinvar id is 5097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132905686-GCTTT-G is described in Lovd as [Pathogenic]. Variant chr9-132905686-GCTTT-G is described in Lovd as [Pathogenic]. Variant chr9-132905686-GCTTT-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSC1	NM_000368.5	c.1888_1891del	p.Lys630GlnfsTer22	frameshift_variant	15/23	ENST00000298552.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSC1	ENST00000298552.9	c.1888_1891del	p.Lys630GlnfsTer22	frameshift_variant	15/23	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

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9 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, no assertion criteria provided	literature only	OMIM	Aug 08, 1997	- -
Pathogenic, criteria provided, single submitter	clinical testing	Division of Genomic Medicine, Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University	Jul 17, 2022	- -
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	Invitae	Jan 16, 2024	This sequence change creates a premature translational stop signal (p.Lys630Glnfs*22) 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 clinical features of tuberous sclerosis complex (PMID: 9242607, 9863590, 9924605, 10533067). This variant is also known as 2105delAAAG and 2109_2112delAAAG. ClinVar contains an entry for this variant (Variation ID: 5097). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 02, 2022	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); Also known as 2105delAAAG; This variant is associated with the following publications: (PMID: 9328481, 9863590, 10533067, 28968464, 29740858, 28991257, 32211034, 32368696, 33278787, 33084842, 32313033, 32005694, 9242607) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 13, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 05, 2020	This variant is expected to result in the loss of a functional protein. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant is also referred to as c.1884_1887delAAAG and c.2105delAAAG in published literature. This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. This variant has been confirmed to occur de novo in one individual with clinical features associated with this gene. -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Oct 05, 2020	This frameshift variant alters the translational reading frame of the TSC1 mRNA and causes the premature termination of TSC1 protein synthesis. It has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals with tuberous sclerosis (PMID: 9242607 (1997), 9924605 (1998), 10363127 (1998), 10227394 (1999), 16981987 (2006), 21510812 (2011), 24271014 (2014)). In addition, this variant was found in the de novo state in an individual with tuberous sclerosis (PMID: 10533067 (1999)). Cased on the available information, this variant is classified as pathogenic. -

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)	-	- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs118203595; hg19: chr9-135781073;