rs118203378

Variant names:

• chr9-132923472-GACA-G
• rs118203378
• NM_000368.5:c.381_383delTGT

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PM4_Supporting PP5_Very_Strong

The NM_000368.5(TSC1):​c.381_383delTGT​(p.Val128del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TSC1 NM_000368.5 disruptive_inframe_deletion
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2 O:2
• Conservation: PhyloP100: 8.70

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 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000368.5. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 9-132923472-GACA-G is Pathogenic according to our data. Variant chr9-132923472-GACA-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 49038.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132923472-GACA-G is described in Lovd as [Pathogenic]. Variant chr9-132923472-GACA-G is described in Lovd as [Pathogenic]. Variant chr9-132923472-GACA-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC1	NM_000368.5	c.381_383delTGT	p.Val128del	disruptive_inframe_deletion	Exon 6 of 23	ENST00000298552.9	NP_000359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC1	ENST00000298552.9	c.381_383delTGT	p.Val128del	disruptive_inframe_deletion	Exon 6 of 23	1	NM_000368.5	ENSP00000298552.3
TSC1	ENST00000490179.4	c.381_383delTGT	p.Val128del	disruptive_inframe_deletion	Exon 7 of 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: Likely pathogenic

Submissions summary: Pathogenic:2 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tuberous sclerosis syndrome Other:2

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Tuberous sclerosis database (TSC1)

Significance: not provided

Review Status: no classification provided

Collection Method: curation

- -

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Tuberous sclerosis database (TSC1)

Significance: not provided

Review Status: no classification provided

Collection Method: curation

- -

Tuberous sclerosis 1 Pathogenic:1

Aug 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.381_383del, results in the deletion of 1 amino acid(s) of the TSC1 protein (p.Val128del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with tuberous sclerosis and/or tuberous sclerosis complex (PMID: 18830229; internal data). It has also been observed to segregate with disease in related individuals. This variant is also known as c.379_381delTGT (p.128delV). ClinVar contains an entry for this variant (Variation ID: 49038). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects TSC1 function (PMID: 21309039). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Jun 27, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.381_383delTGT variant (also known as p.V128del) is located in coding exon 4 of the TSC1 gene. This variant results from an in-frame TGT deletion at nucleotide positions 381 to 383. This results in the in-frame deletion of a valine at codon 128. This variant has been reported in individuals with features consistent with a clinical diagnosis of tuberous sclerosis complex (TSC) (Nellist M et al. Eur J Hum Genet, 2009 Mar;17:319-28; external communication). In addition, this alteration was identified in 1 of 374 patients with clinically suspected TSC undergoing genetic testing within the TSC1 and TSC2 genes (Meng Y et al. J Hum Genet, 2021 Mar;66:227-236). Functional studies have reported a deleterious impact for this variant (Nellist M et al. Eur J Hum Genet, 2009 Mar;17:319-28; Hoogeveen-Westerveld M et al. Hum Mutat, 2011 Apr;32:424-35). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Based on the majority of available evidence to date, this variant is likely to be 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: rs118203378; hg19: chr9-135798859;