Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong
The NM_000548.5(TSC2):c.1599+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 0.028761063 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 16-2064428-G-A is Pathogenic according to our data. Variant chr16-2064428-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 49646.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2064428-G-A is described in Lovd as [Pathogenic]. Variant chr16-2064428-G-A is described in Lovd as [Pathogenic].
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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not provided Pathogenic:1
Aug 24, 2022
Athena Diagnostics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This variant is expected to severely impact normal RNA splicing, and consequently, protein structure and/or function. This variant has been identified in at least one individual with clinical features associated with this gene. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). -
Review Status: criteria provided, single submitter
Collection Method: clinical testing
The c.1599+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 14 of the TSC2 gene. This alteration was detected once in a cohort of individuals with definite, probable, or possible diagnoses of tuberous sclerosis complex (Au KS et al. Genet. Med., 2007 Feb;9:88-100). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation. -