Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PM5PP3_Strong
The NM_000548.5(TSC2):c.2150T>A(p.Leu717Gln) variant causes a missense 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. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L717R) has been classified 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 Likely_pathogenic. Variant got 8 ACMG points.
PM2
?
PM2 - Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
Very rare variant in population databases, with high coverage;
PM5
?
PM5 - Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before
Other missense variant is known to change same aminoacid residue: Variant chr16-2072293-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 12398.Status of the report is no_assertion_criteria_provided, 0 stars.
PP3
?
PP3 - Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.)
MetaRNN computational evidence supports a deleterious effect, 0.986
Gain of methylation at K720 (P = 0.0365);Gain of methylation at K720 (P = 0.0365);Gain of methylation at K720 (P = 0.0365);.;Gain of methylation at K720 (P = 0.0365);Gain of methylation at K720 (P = 0.0365);Gain of methylation at K720 (P = 0.0365);Gain of methylation at K720 (P = 0.0365);.;Gain of methylation at K720 (P = 0.0365);Gain of methylation at K720 (P = 0.0365);Gain of methylation at K720 (P = 0.0365);Gain of methylation at K720 (P = 0.0365);Gain of methylation at K720 (P = 0.0365);.;