Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PVS1PM2PP3PP5_Moderate
The NM_000368.5(TSC1):c.912T>G(p.Tyr304*) variant causes a stop gained, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. Y304Y) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
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]
TSC1 Gene-Disease associations (from GenCC):
tuberous sclerosis
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
tuberous sclerosis 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, PanelApp Australia, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)
lung 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 13 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;
PP3
Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
PP5
Variant 9-132912283-A-C is Pathogenic according to our data. Variant chr9-132912283-A-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 49122.Status of the report is criteria_provided_single_submitter, 1 stars.
Human Genome Lab, NIMHANS, National Institute of Mental Health and Neuro Sciences
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
The stop gained NM_000368.5(TSC1):c.912T>G (p.Tyr304Ter) has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Tyr304Ter variant is novel (not in any individuals) in 1kG All. The p.Tyr304Ter variant is novel (not in any individuals) in gnomAD as well as in our inhouse database. The variant was previously reported in ClinVar database with no assertion criteria (Accession: VCV000049122.2). This variant is predicted to cause loss of normal protein function through protein truncation. This variant is a stop gained variant which occurs in an exon of TSC1 upstream of where nonsense mediated decay is predicted to occur. There are 282 downstream pathogenic loss of function variants, with the furthest variant being 652 residues downstream of this variant. This indicates that the region is critical to protein function. The gene TSC1 has a low rate of benign loss of function variants as indicated by a low upper bound of the observed/expected confidence interval 0.12. The p.Tyr304Ter variant is a loss of function variant in the gene TSC1, which is intolerant of Loss of Function variants, as indicated by the presence of existing pathogenic loss of function variant NP_000359.1:p.Q4* and 343 others. For these reasons, this variant has been classified as Likely Pathogenic. -