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).1 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.2 In silico analysis with REVEL (score 0.786) predicts a deleterious effect, though BayesDel (0.134) is discordant (PP3).3 SpliceAI predicts no splice impact (max delta = 0.00).4 This variant has been reported in ClinVar as Uncertain significance by a single clinical laboratory (Labcorp/Invitae, SCV002596392). No expert panel review is available.5 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.6 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).
CBL
Final classification
VUS
CBL c.1147A>C · p.Ile383Leu
CBL
NM_005188.3:c.1147A>C (p.Ile383Leu) is a missense variant in exon 8 of the CBL gene.
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM1 moderate, PM2 supporting, PP3 supporting; combination = 1 moderate + 2 supporting, which maps to VUS.
Classification rationale
PM1PM2PP3
VUS
CBL c.1147A>C
PM1 + PM2 + PP3
→
VUS
Gene diagram
· NM_005188.3 · variants mapped to exon structure
CBL
NM_005188.3
Fetching transcript structure from UCSC…
Applied criteria · 3 applied · 18 assessed
Applied · 3
Strength
Supporting
Moderate
Strong
Very strong
✓
PM1
moderate
Pathogenic
This variant is located in the CBL RING finger domain (residues 381-420), a critical and well-established functional domain. Missense variants in this domain are a known disease mechanism for CBL-related disorders (Noonan-like syndrome/CBL syndrome), which has a recognized germline disease association. UniProt confirms residue 383 lies within the RING-type zinc finger domain.
Located in CBL RING finger domain (residues 381-420)RING domain is a critical functional domain with established pathogenic missense variantsGermline CBL disease context supported by literature (PMID:25952305)
✓
PM2
supporting
Pathogenic
This variant is extremely rare in population databases. In gnomAD v2.1 it is observed at an allele frequency of 3.98x10^-6 (1/251,292 alleles, 0 homozygotes), and in gnomAD v4.1 at 6.20x10^-7 (1/1,612,068 alleles, 0 homozygotes). Both frequencies are well below the 0.1% threshold for PM2. The variant is absent from gnomAD-Canada v1.0.
gnomAD v2.1 AF = 3.98e-06 (<0.1%)gnomAD v4.1 AF = 6.20e-07 (<0.1%)Absent from gnomAD-Canada
✓
PP3
supporting
Pathogenic
REVEL predicts a deleterious effect with a score of 0.786, which is above the established pathogenic threshold (>0.5). However, BayesDel (0.134) is discordant and does not support pathogenicity. SpliceAI predicts no splicing impact (max delta = 0.00). In silico evidence is mixed but the REVEL meta-predictor strongly supports a damaging effect.
REVEL = 0.786 (deleterious)BayesDel = 0.134 (benign-leaning)SpliceAI max delta = 0.00
Assessed · not applied
Pathogenic
PS1
No evidence of a different nucleotide change at codon 383 (c.1147) predicting the same missense change (p.Ile383Leu) with an established pathogenic classification.
PS2
No de novo occurrence of NM_005188.3:c.1147A>C has been reported in the literature or in ClinVar.
PS3
No well-established functional studies demonstrate a damaging effect for this exact variant.
PS4
No case-control data or statistically significant enrichment in affected individuals versus controls is available.
PM5
PM5 candidate harvesting found no same-residue comparator variants for residue 383.
PM6
No assumed de novo observations have been reported for this variant.
PP1
No segregation data are available for this variant.
PP2
PP2 requires a missense variant in a gene with a low rate of benign missense variation and where missense variants are a common disease mechanism.
PP4
PP4 requires the patient's phenotype or family history to be highly specific for a disease with a single genetic etiology.
PP5
No reputable source reports this variant as pathogenic.
Benign
BA1
BA1 requires an allele frequency >1% in population databases.
BS1
BS1 requires an allele frequency >0.3% in population databases.
BS2
While the variant is observed in 1 heterozygous individual in each of gnomAD v2.1 and v4.1 (which are general population databases), the phenotype of these individuals is unknown.
BS3
No well-established functional studies demonstrate a neutral or benign effect for this variant.
BS4
BS4 requires lack of segregation in affected family members.
BP4
BP4 requires multiple lines of computational evidence suggesting no impact.
BP5
BP5 requires the variant to be found in a case with an alternate molecular basis for disease.
BP6
No reputable source reports this variant as benign.
N/A · 4
PVS1 · BP1 · BP2 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 6.20321e-07; MAF= 0.00006%, 1/1612068 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 1.66644e-05; MAF= 0.00167%, 1/60008 alleles, homozygotes = 0).
v2.1
This variant is present in gnomAD v2.1 (AF= 3.97943e-06; MAF= 0.00040%, 1/251292 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 2.89118e-05; MAF= 0.00289%, 1/34588 alleles, homozygotes = 0).
🇨🇦 CA
This variant is absent from gnomAD-Canada.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
6.2e-05%
· 1 / 1,612,068
0 hom
0 hom
Admixed American 1 / 60,008 |
0.0017% |
+ 9 not observed (Remaining individuals, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American, European (non-Finnish))
gnomAD v2.1
0.0004%
· 1 / 251,292
0 hom
0 hom
Admixed American 1 / 34,588 |
0.0029% |
+ 7 not observed (African/African American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals, South Asian)
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory). (ClinVarID = 1716702)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.786. BayesDel score = 0.134053.
Functional
Unknown Oncogenic Effect
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. CBL, a tumor suppressor and ubiquitin ligase, is inactivated by mutation or deletion in various cancer types including myeloid malignancies.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
Triaged references · 1 PMID not cited in assessment
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR