Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong
The NM_000548.5(TSC2):c.774+1G>A variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as 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 12 ACMG points.
PVS1
Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.023230089 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 16-2056770-G-A is Pathogenic according to our data. Variant chr16-2056770-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 49919.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2056770-G-A is described in Lovd as [Pathogenic]. Variant chr16-2056770-G-A is described in Lovd as [Pathogenic].
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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Dec 24, 2019
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
For these reasons, this variant has been classified as Pathogenic. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in TSC2 are known to be pathogenic (PMID: 10205261, 17304050). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Disruption of this splice site has been observed in individual(s) with tuberous sclerosis complex (PMID: 10735580, 15798777, 17304050, 29101226). In at least one individual the splice site variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 49919). This variant is not present in population databases (ExAC no frequency). This sequence change affects a donor splice site in intron 8 of the TSC2 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. -
not provided Pathogenic:1
Oct 02, 2019
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
Canonical splice site variant predicted to result in an in-frame deletion of a critical region; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 29975249, 15798777, 17304050, 25525159) -