rs137853983

Variant names:

• chr16-2062519-TCTC-T
• rs137853983
• NM_000548.5:c.1283_1285delCCT

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM2 PM4_Supporting PP5_Very_Strong

The NM_000548.5(TSC2):​c.1283_1285delCCT​(p.Ser428del) 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 (★★). Synonymous variant affecting the same amino acid position (i.e. S428S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TSC2 NM_000548.5 disruptive_inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5 O:1
• Conservation: PhyloP100: 7.59
• Publications: 1 publications found

Genes affected

TSC2 (HGNC:12363): (TSC complex subunit 2) This gene is a tumor suppressor gene that encodes the growth inhibitory protein tuberin. Tuberin interacts with hamartin to form the TSC protein complex which functions in the control of cell growth. This TSC protein complex negatively regulates mammalian target of rapamycin complex 1 (mTORC1) signaling which is a major regulator of anabolic cell growth. Mutations in this gene have been associated with tuberous sclerosis and lymphangioleiomyomatosis. [provided by RefSeq, May 2022]

TSC2 Gene-Disease associations (from GenCC):

• tuberous sclerosis

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• tuberous sclerosis 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, Ambry Genetics
• lymphangioleiomyomatosis

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• tuberous sclerosis complex

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000548.5. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 16-2062519-TCTC-T is Pathogenic according to our data. Variant chr16-2062519-TCTC-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 49644.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC2	NM_000548.5	c.1283_1285delCCT	p.Ser428del	disruptive_inframe_deletion	Exon 13 of 42	ENST00000219476.9	NP_000539.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9	c.1283_1285delCCT	p.Ser428del	disruptive_inframe_deletion	Exon 13 of 42	5	NM_000548.5	ENSP00000219476.3

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tuberous sclerosis 2 Pathogenic:2

Jan 26, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.1283_1285del, results in the deletion of 1 amino acid(s) of the TSC2 protein (p.Ser428del), 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 clinical features of tuberous sclerosis complex (PMID: 17304050, 21520333, 22867869, 32555378; internal data). ClinVar contains an entry for this variant (Variation ID: 49644). 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 TSC2 function (PMID: 32555378). 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. -

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Oasi Research Institute-IRCCS

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

Variant c.1283_1285delCCT is an in-frame deletion. ACMG criteria: PP4 (phenotype match), PM2 (absent from control), PS2 (de novo); PP5 (source without evidence) = Pathogenic. Based on the evidence outlined above, the variant was classified as Pathogenic. -

not provided Pathogenic:2

Aug 27, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The TSC2 c.1283_1285del, p.Ser428del variant (rs137853983; ClinVar Variation ID: 49644), has been previously published following identification in at least three individuals included in screening cohorts for TSC2-related clinical presentations (Au 2007, Rosengren 2020, van Eeghen 2013). Functional evaluation in heterologous cell culture indicates this variant disrupts TSC complex activity as measured by increased downstream mTOR activity (Rosengren 2020). This variant is also absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. Based on the available information, the p.Ser428del variant is considered likely pathogenic. References: Au KS et al. Genotype/phenotype correlation in 325 individuals referred for a diagnosis of tuberous sclerosis complex in the United States. Genet Med. 2007 Feb;9(2):88-100. Rosengren et al. Mutational analysis of TSC1 and TSC2 in Danish patients with tuberous sclerosis complex. Sci Rep. 2020 Jun 18;10(1):9909. van Eeghen AM et al. Central TSC2 missense mutations are associated with a reduced risk of infantile spasms. Epilepsy Res. 2013 Jan;103(1):83-7. -

Apr 18, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in multiple unrelated individuals with a clinical diagnosis of TSC, including as an assumed de novo variant in two individuals with TSC (Au et al., 2007; van Eeghen et al., 2013; TSC2 LOVD); Published functional studies demonstrate a damaging effect on TSC complex formation and TSC complex dependent inhibition of mTORC1 activity (Rosengren et al., 2020; TSC2 LOVD); Not observed at significant frequency in large population cohorts (gnomAD); In-frame deletion of a single amino acid in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 17304050, 21520333, 32917966, 32555378, 22867869, LOVD) -

TSC2-related disorder Pathogenic:1

Mar 06, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The TSC2 c.1283_1285delCCT variant is predicted to result in an in-frame deletion (p.Ser428del). This variant was reported in four individuals with suspected tuberous sclerosis complex (TSC; Supplement, Au et al. 2007. PubMed ID: 17304050; Table S1, van Eeghen et al. 2012. PubMed ID: 22867869; Table 2, Rosengren et al. 2020. PubMed ID: 32555378; Table S1, Referred to as TSC2:p.427_428del, Meng et al. 2021. PubMed ID: 32917966). In one of these individuals this variant was reported as a low level mosaic finding (Read Frequency of 8%; Table 2, Rosengren et al. 2020. PubMed ID: 32555378). In another one of these individuals, the variant was maternally inherited and the TSC diagnosis was uncertain (Table S1, Referred to as TSC2:p.427_428del, Meng et al. 2021. PubMed ID: 32917966). This variant has been reported in multiple probands in the Leiden Open Database, several of whom inherited the variant (https://databases.lovd.nl/shared/view/TSC2?search_VariantOnGenome%2FDBID=%3D%22TSC2_000813%22). This variant has been reported in three additional unrelated individuals undergoing TSC genetic testing with clinical features consistent with TSC (PreventionGenetics LLC, Internal Data). In vitro functional studies suggest this variant leads to disrupted TSC-complex function (Figure 2, Table 3, Rosengren et al. 2020. PubMed ID: 32555378). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. It is interpreted as pathogenic and likely pathogenic in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/49644/). This variant is interpreted as likely pathogenic. -

Tuberous sclerosis syndrome Other:1

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Tuberous sclerosis database (TSC2)

Significance: not provided

Review Status: no classification provided

Collection Method: curation

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.6
Mutation Taster		=72/28	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs137853983; hg19: chr16-2112520;