Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_000548.5(TSC2):c.5140delC(p.Gln1714ArgfsTer112) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. 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. Q1714Q) has been classified as Benign. Variant results in nonsense mediated mRNA decay.
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
Our verdict: Pathogenic. The variant received 12 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 16-2088117-GC-G is Pathogenic according to our data. Variant chr16-2088117-GC-G is described in CliVar as Pathogenic. Clinvar id is 238075.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2088117-GC-G is described in CliVar as Pathogenic. Clinvar id is 238075.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2088117-GC-G is described in CliVar as Pathogenic. Clinvar id is 238075.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2088117-GC-G is described in CliVar as Pathogenic. Clinvar id is 238075.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2088117-GC-G is described in CliVar as Pathogenic. Clinvar id is 238075.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2088117-GC-G is described in CliVar as Pathogenic. Clinvar id is 238075.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2088117-GC-G is described in CliVar as Pathogenic. Clinvar id is 238075.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2088117-GC-G is described in CliVar as Pathogenic. Clinvar id is 238075.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2088117-GC-G is described in CliVar as Pathogenic. Clinvar id is 238075.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2088117-GC-G is described in CliVar as Pathogenic. Clinvar id is 238075.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2088117-GC-G is described in CliVar as Pathogenic. Clinvar id is 238075.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2088117-GC-G is described in CliVar as Pathogenic. Clinvar id is 238075.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2088117-GC-G is described in CliVar as Pathogenic. Clinvar id is 238075.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2088117-GC-G is described in CliVar as Pathogenic. Clinvar id is 238075.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2088117-GC-G is described in CliVar as Pathogenic. Clinvar id is 238075.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2088117-GC-G is described in CliVar as Pathogenic. Clinvar id is 238075.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2088117-GC-G is described in CliVar as Pathogenic. Clinvar id is 238075.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2088117-GC-G is described in CliVar as Pathogenic. Clinvar id is 238075.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2088117-GC-G is described in CliVar as Pathogenic. Clinvar id is 238075.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2088117-GC-G is described in CliVar as Pathogenic. Clinvar id is 238075.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2088117-GC-G is described in CliVar as Pathogenic. Clinvar id is 238075.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2088117-GC-G is described in CliVar as Pathogenic. Clinvar id is 238075.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2088117-GC-G is described in CliVar as Pathogenic. Clinvar id is 238075.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2088117-GC-G is described in CliVar as Pathogenic. Clinvar id is 238075.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2088117-GC-G is described in CliVar as Pathogenic. Clinvar id is 238075.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2088117-GC-G is described in CliVar as Pathogenic. Clinvar id is 238075.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2088117-GC-G is described in CliVar as Pathogenic. Clinvar id is 238075.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2088117-GC-G is described in CliVar as Pathogenic. Clinvar id is 238075.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2088117-GC-G is described in CliVar as Pathogenic. Clinvar id is 238075.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2088117-GC-G is described in CliVar as Pathogenic. Clinvar id is 238075.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2088117-GC-G is described in CliVar as Pathogenic. Clinvar id is 238075.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2088117-GC-G is described in CliVar as Pathogenic. Clinvar id is 238075.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2088117-GC-G is described in CliVar as Pathogenic. Clinvar id is 238075.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2088117-GC-G is described in CliVar as Pathogenic. Clinvar id is 238075.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2088117-GC-G is described in CliVar as Pathogenic. Clinvar id is 238075.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2088117-GC-G is described in CliVar as Pathogenic. Clinvar id is 238075.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2088117-GC-G is described in CliVar as Pathogenic. Clinvar id is 238075.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2088117-GC-G is described in CliVar as Pathogenic. Clinvar id is 238075.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2088117-GC-G is described in CliVar as Pathogenic. Clinvar id is 238075.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2088117-GC-G is described in CliVar as Pathogenic. Clinvar id is 238075.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2088117-GC-G is described in CliVar as Pathogenic. Clinvar id is 238075.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2088117-GC-G is described in CliVar as Pathogenic. Clinvar id is 238075.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2088117-GC-G is described in CliVar as Pathogenic. Clinvar id is 238075.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2088117-GC-G is described in CliVar as Pathogenic. Clinvar id is 238075.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2088117-GC-G is described in CliVar as Pathogenic. Clinvar id is 238075.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2088117-GC-G is described in CliVar as Pathogenic. Clinvar id is 238075.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2088117-GC-G is described in CliVar as Pathogenic. Clinvar id is 238075.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2088117-GC-G is described in CliVar as Pathogenic. Clinvar id is 238075.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2088117-GC-G is described in CliVar as Pathogenic. Clinvar id is 238075.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2088117-GC-G is described in CliVar as Pathogenic. Clinvar id is 238075.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2088117-GC-G is described in CliVar as Pathogenic. Clinvar id is 238075.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2088117-GC-G is described in CliVar as Pathogenic. Clinvar id is 238075.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2088117-GC-G is described in CliVar as Pathogenic. Clinvar id is 238075.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2088117-GC-G is described in CliVar as Pathogenic. Clinvar id is 238075.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2088117-GC-G is described in CliVar as Pathogenic. Clinvar id is 238075.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2088117-GC-G is described in CliVar as Pathogenic. Clinvar id is 238075.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2088117-GC-G is described in CliVar as Pathogenic. Clinvar id is 238075.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2088117-GC-G is described in CliVar as Pathogenic. Clinvar id is 238075.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2088117-GC-G is described in CliVar as Pathogenic. Clinvar id is 238075.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2088117-GC-G is described in CliVar as Pathogenic. Clinvar id is 238075.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2088117-GC-G is described in CliVar as Pathogenic. Clinvar id is 238075.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2088117-GC-G is described in CliVar as Pathogenic. Clinvar id is 238075.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2088117-GC-G is described in CliVar as Pathogenic. Clinvar id is 238075.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2088117-GC-G is described in CliVar as Pathogenic. Clinvar id is 238075.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2088117-GC-G is described in CliVar as Pathogenic. Clinvar id is 238075.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2088117-GC-G is described in CliVar as Pathogenic. Clinvar id is 238075.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2088117-GC-G is described in CliVar as Pathogenic. Clinvar id is 238075.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2088117-GC-G is described in CliVar as Pathogenic. Clinvar id is 238075.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2088117-GC-G is described in CliVar as Pathogenic. Clinvar id is 238075.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2088117-GC-G is described in CliVar as Pathogenic. Clinvar id is 238075.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2088117-GC-G is described in CliVar as Pathogenic. Clinvar id is 238075.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2088117-GC-G is described in CliVar as Pathogenic. Clinvar id is 238075.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2088117-GC-G is described in CliVar as Pathogenic. Clinvar id is 238075.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2088117-GC-G is described in CliVar as Pathogenic. Clinvar id is 238075.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2088117-GC-G is described in CliVar as Pathogenic. Clinvar id is 238075.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2088117-GC-G is described in CliVar as Pathogenic. Clinvar id is 238075.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2088117-GC-G is described in CliVar as Pathogenic. Clinvar id is 238075.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2088117-GC-G is described in CliVar as Pathogenic. Clinvar id is 238075.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2088117-GC-G is described in CliVar as Pathogenic. Clinvar id is 238075.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2088117-GC-G is described in CliVar as Pathogenic. Clinvar id is 238075.Status of the report is criteria_provided_single_submitter, 1 stars.
This variant disrupts the C-terminus of the TSC2 protein. Other variant(s) that disrupt this region (p.Pro1784Alafs*? and p.Phe1803Leufs*42) have been determined to be pathogenic (PMID: 10205261, 9328481, 24789117). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals with TSC2-related conditions. ClinVar contains an entry for this variant (Variation ID: 238075). This variant is not present in population databases (ExAC no frequency). This sequence change results in a frameshift in the TSC2 gene (p.Gln1714Argfs*112). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 94 amino acid(s) of the TSC2 protein and extend the protein by 17 additional amino acid residues. -