Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2PM5PP2PP3_Strong
The NM_000368.5(TSC1):c.278T>G(p.Leu93Arg) 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 not provided (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L93P) 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]
Verdict is Likely_pathogenic. Variant got 9 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 chr9-132925672-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 974549.Status of the report is criteria_provided_single_submitter, 1 stars.
PP2
?
PP2 - Missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease
Missense variant where missense usually causes diseases, TSC1
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, 0.982
Gain of methylation at L93 (P = 0.0036);Gain of methylation at L93 (P = 0.0036);Gain of methylation at L93 (P = 0.0036);Gain of methylation at L93 (P = 0.0036);Gain of methylation at L93 (P = 0.0036);Gain of methylation at L93 (P = 0.0036);Gain of methylation at L93 (P = 0.0036);Gain of methylation at L93 (P = 0.0036);Gain of methylation at L93 (P = 0.0036);Gain of methylation at L93 (P = 0.0036);Gain of methylation at L93 (P = 0.0036);Gain of methylation at L93 (P = 0.0036);Gain of methylation at L93 (P = 0.0036);Gain of methylation at L93 (P = 0.0036);Gain of methylation at L93 (P = 0.0036);Gain of methylation at L93 (P = 0.0036);