NM_005188.3:c.1147A>C (p.Ile383Leu) is a missense variant in exon 8 of the CBL gene.
This variant is located in the CBL RING finger domain (residues 381-420), a critical functional domain where missense variants are an established disease mechanism for Noonan-like syndrome/CBL syndrome (PM1).
It is extremely rare in population databases: observed in 1 of 251,292 alleles in gnomAD v2.1 (AF=3.98x10^-6) and 1 of 1,612,068 alleles in gnomAD v4.1 (AF=6.20x10^-7), with no homozygotes in any population dataset, meeting PM2 criteria.
gnomad_v2 ↗ gnomad_v4 ↗In silico analysis with REVEL (score 0.786) predicts a deleterious effect, though BayesDel (0.134) is discordant (PP3).
SpliceAI predicts no splice impact (max delta = 0.00).
spliceai ↗This variant has been reported in ClinVar as Uncertain significance by a single clinical laboratory (Labcorp/Invitae, SCV002596392). No expert panel review is available.
clinvar ↗No functional studies, segregation data, case-control analyses, or de novo observations have been reported for this variant in the literature.
OncoKB classifies this variant as having Unknown Oncogenic Effect.
oncokb ↗The variant has not been reported in COSMIC and does not lie in a statistically significant cancer hotspot.
Overall, applying generic ACMG/AMP 2015 criteria, the evidence is limited to PM1 (moderate) + PM2 (supporting) + PP3 (supporting). No benign criteria are met. This is insufficient to reach a likely pathogenic classification (requires at least 2 moderate or 1 strong). The variant remains a Variant of Uncertain Significance (VUS).
