Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PS1PM1PM2PP3
The NM_000548.5(TSC2):c.2436C>A(p.Ser812Arg) variant causes a missense 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin Lovd. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S812G) has been classified as Uncertain significance.
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 9 ACMG points.
PS1
?
PS1 - Same amino acid change as a previously established pathogenic variant regardless of nucleotide change
Transcript NM_000548.5 (TSC2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
PM1
?
PM1 - Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 6 benign, 13 uncertain in NM_000548.5
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;
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, 0.767
Loss of catalytic residue at S809 (P = 0.0623);Loss of catalytic residue at S809 (P = 0.0623);Loss of catalytic residue at S809 (P = 0.0623);.;Loss of catalytic residue at S809 (P = 0.0623);Loss of catalytic residue at S809 (P = 0.0623);Loss of catalytic residue at S809 (P = 0.0623);Loss of catalytic residue at S809 (P = 0.0623);.;Loss of catalytic residue at S809 (P = 0.0623);Loss of catalytic residue at S809 (P = 0.0623);Loss of catalytic residue at S809 (P = 0.0623);Loss of catalytic residue at S809 (P = 0.0623);Loss of catalytic residue at S809 (P = 0.0623);.;