Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP2PP3_Moderate
The NM_000368.5(TSC1):āc.358C>Gā(p.Leu120Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,866 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. L120I) has been classified as Uncertain significance.
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]
Loss of catalytic residue at L120 (P = 0.0325);Loss of catalytic residue at L120 (P = 0.0325);Loss of catalytic residue at L120 (P = 0.0325);Loss of catalytic residue at L120 (P = 0.0325);Loss of catalytic residue at L120 (P = 0.0325);Loss of catalytic residue at L120 (P = 0.0325);Loss of catalytic residue at L120 (P = 0.0325);Loss of catalytic residue at L120 (P = 0.0325);Loss of catalytic residue at L120 (P = 0.0325);Loss of catalytic residue at L120 (P = 0.0325);Loss of catalytic residue at L120 (P = 0.0325);Loss of catalytic residue at L120 (P = 0.0325);Loss of catalytic residue at L120 (P = 0.0325);Loss of catalytic residue at L120 (P = 0.0325);Loss of catalytic residue at L120 (P = 0.0325);Loss of catalytic residue at L120 (P = 0.0325);