Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_000548.5(TSC2):c.5252_5259+19delGCCAGCGGGTAGGGAATATGGGGCTCC(p.Arg1751ProfsTer51) variant causes a frameshift, splice donor, splice region, intron 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 (★★).
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]
Verdict is Pathogenic. Variant got 14 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 18 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 16-2088311-CGGCTCCGCCAGCGGGTAGGGAATATGG-C is Pathogenic according to our data. Variant chr16-2088311-CGGCTCCGCCAGCGGGTAGGGAATATGG-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 49366.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2088311-CGGCTCCGCCAGCGGGTAGGGAATATGG-C is described in Lovd as [Pathogenic]. Variant chr16-2088311-CGGCTCCGCCAGCGGGTAGGGAATATGG-C is described in Lovd as [Pathogenic].
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This variant results in the deletion of part of exon 41 (c.5252_5252+19) of the TSC2 gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with tuberous sclerosis complex (PMID: 11112665, 21520333, 25498131). ClinVar contains an entry for this variant (Variation ID: 49366). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). This variant disrupts a region of the TSC2 protein in which other variant(s) (p.Ser1761Leufs*60) have been determined to be pathogenic (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
May 03, 2013
Athena Diagnostics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
- -
Jul 07, 2023
3billion
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Canonical splice site: predicted to alter splicing and result in a loss or disruption of normal protein function. The predicted truncated protein may be shortened by less than 10%. The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 11112665, 16981987, 27406250). The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000049366 /PMID: 11112665). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
Nov 07, 2021
Genome-Nilou Lab
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
- -
not provided Pathogenic:2
Jan 02, 2025
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown.; Deletions involving coding exons of this gene are a known mechanism of disease (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 16981987, 27406250, 25498131, 18466115, 36674629, 21520333, 11112665) -
Jun 20, 2023
Mayo Clinic Laboratories, Mayo Clinic
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
PP4, PM2_moderate, PM6, PS4, PVS1_strong -
Lymphangiomyomatosis;C1846385:Isolated focal cortical dysplasia type II;C1860707:Tuberous sclerosis 2 Pathogenic:1
Jan 04, 2024
Fulgent Genetics, Fulgent Genetics
Significance: Likely pathogenic
Review Status: criteria provided, single submitter