CBL c.1147A>C, p.Ile383Leu
NM_005188.3:c.1147A>C
Population Frequency
0.000398%
Rare
ClinVar Classification
Uncertain Significance (VUS)
0 publications
REVEL Score
0.786
Likely Pathogenic
COSMIC Recurrence
0 occurrences
No Criteria Applied
Classification Evidence
Detailed Information
Genetic Information
Gene & Transcript Details
Gene
CBL
Transcript
NM_005188.4
MANE Select
Total Exons
16
Strand
Forward (+)
Reference Sequence
NC_000011.9
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_005188.3 | RefSeq Select | 16 exons | Forward |
| NM_005188.2 | Alternative | 16 exons | Forward |
Variant Details
HGVS Notation
NM_005188.3:c.1147A>C
Protein Change
I383L
Location
Exon 8
(Exon 8 of 16)
5'
Exon Structure (16 total)
3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 383 in gene CBL
Variant interpretation based on transcript NM_005188.4
Clinical Evidence
Global Frequency
0.000398%
Extremely Rare
Highest in Population
Admixed American
0.00289%
Rare
Global: 0.000398%
Admixed American: 0.00289%
0%
0.0005%
0.001%
0.01%
0.05%
1%+
Allele Information
Total: 251292
Alt: 1
Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.000398%, 1/251292 alleles, homozygotes = 0) and at a higher frequency in the Admixed American population (MAF= 0.00289%, 1/34588 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
Uncertain Significance (VUS)
Based on 1 submitter review in ClinVar
Submitter Breakdown
Pathogenic
Likely Pathogenic
VUS
Likely Benign
Benign
Publications
0 publications
Clinical Statement
This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratories).
Functional Domain
Hotspot Status
Not a hotspot
Domain Summary
This variant is not located in a mutational hotspot or critical domain (0 mutations).
Related Variants in This Domain
No evidence of other pathogenic variants at position 383 in gene CBL
Functional Studies
Summary
The CBL I383L variant results in a loss of E3 ubiquitin ligase activity, is transforming in cell culture, and promotes tumor formation in animal models, indicating a damaging effect.
Computational Evidence
Pathogenicity Predictions
REVEL Score
0.786
0.786
Likely Benign
0.0
Uncertain (Low)
0.2
Uncertain (Med)
0.5
Likely Pathogenic
0.75
REVEL scores ≥ 0.75 are considered strong evidence of pathogenicity (PP3)
Predictor Consensus
Mixed/VUS
PP3 Applied
Yes
Additional Predictors
Pathogenic:
polyphen_prediction: probably_damaging
mutationtaster: D
metasvm: D
metalr: D
primateai: D
Benign:
CADD: 5.32
Neutral:
Show all
VCEP Guidelines
Applied ACMG/AMP Criteria
PVS1
PVS1 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PVS1 is: 'Null variant in a gene where loss of function (LoF) is a known mechanism of disease'. The evidence for this variant shows: It is a missense variant (I383L) rather than a null variant. Therefore, this criterion is not applied at Not Applied strength because the variant type does not meet the null variant requirement.
PS1
PS1 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PS1 is: 'Same amino acid change as a known pathogenic variant but different nucleotide change'. The evidence for this variant shows: There is no reported instance of the same amino acid change arising from a different nucleotide substitution. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PS2 is: 'De novo (both maternity and paternity confirmed) in a patient with the disease and no family history'. The evidence for this variant shows: There is no data indicating a confirmed de novo occurrence. Therefore, this criterion is not applied.
PS3
PS3 (Strong)
According to PTEN Pre-processing guidelines, the rule for PS3 is: 'Well-established functional studies supportive of a damaging effect on the gene or gene product'. The evidence for this variant shows: Functional studies demonstrate loss of E3 ubiquitin ligase activity, transformation in cell culture, and promotion of tumor formation in animal models for the CBL I383L variant. Therefore, this criterion is applied at Strong strength.
PS4
PS4 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PS4 is: 'Prevalence in affected individuals significantly increased compared with controls'. The evidence for this variant shows: No case-control comparison data are available to support an increased prevalence in affected individuals. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PM1 is: 'Located in a mutational hot spot or well-established functional domain without benign variation'. The evidence for this variant shows: There is no specific information indicating that I383 is located within a mutational hotspot or a critical functional domain exclusive of benign variation. Therefore, this criterion is not applied.
PM2
PM2 (Moderate)
According to standard ACMG guidelines, the rule for PM2 is: 'Absent from controls (or at extremely low frequency if recessive)'. The evidence for this variant shows: The minor allele frequency is extremely low (MAF = 0.000398%), which is well below the threshold expected for a benign variant. Therefore, this criterion is applied at Moderate strength.
PM3
PM3 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PM3 is: 'Detected in trans with a pathogenic variant (for recessive disorders)'. The evidence for this variant shows: There is no information indicating that this variant is found in trans with another pathogenic variant. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PM4 is: 'Protein length changes due to in-frame deletions/insertions or stop-loss variants'. The evidence for this variant shows: It is a missense change and does not lead to a change in protein length. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PM5 is: 'Novel missense change at an amino acid residue where a different pathogenic missense change has been seen'. The evidence for this variant shows: There is no report of another pathogenic missense change at the same amino acid residue. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PM6 is: 'Assumed de novo, but without confirmation of paternity and maternity'. The evidence for this variant shows: No de novo occurrence information is provided. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PP1 is: 'Co-segregation with disease in multiple affected family members'. The evidence for this variant shows: There is no segregation data available to support co-segregation with disease. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PP2 is: 'Missense variant in a gene with a low rate of benign missense variation and where missense variants are a common mechanism of disease'. The evidence for this variant shows: While the variant is missense, no specific evidence regarding the gene’s overall intolerance to missense variation is provided beyond other computational assessments. Therefore, this criterion is not applied.
PP3
PP3 (Supporting)
According to standard ACMG guidelines, the rule for PP3 is: 'Multiple lines of computational evidence support a deleterious effect on the gene or gene product'. The evidence for this variant shows: Several computational tools, particularly a REVEL score of 0.79 along with additional in silico predictions, suggest a damaging effect for the variant. Therefore, this criterion is applied at Supporting strength.
PP4
PP4 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: 'Patient's phenotype or family history highly specific for a disease with a single genetic etiology'. The evidence for this variant shows: There is no specific phenotype or family history provided that aligns with a unique genetic disorder linked to this variant. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: 'Reputable source reports variant as pathogenic, but without accessible evidence'. The evidence for this variant shows: Although one clinical laboratory in ClinVar reports the variant as of uncertain significance, there is no reputable source with clear evidence classifying it as pathogenic. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BA1 is: 'Allele frequency is too high for the disorder (stand-alone evidence)'. The evidence for this variant shows: The allele frequency is extremely low and does not meet the high frequency threshold required for BA1. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BS1 is: 'Allele frequency is greater than expected for the disorder'. The evidence for this variant shows: The variant’s frequency is far below the threshold expected for a benign variant. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BS2 is: 'Observed in healthy individuals with full penetrance expected at an early age'. The evidence for this variant shows: There is no indication that the variant is observed in healthy individuals in a manner that contradicts pathogenicity. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BS3 is: 'Well-established functional studies show no damaging effect on protein function or splicing'. The evidence for this variant shows: Functional studies clearly indicate a damaging effect. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BS4 is: 'Lack of segregation in affected family members'. The evidence for this variant shows: No segregation data is provided. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: 'Missense variant in a gene where only LoF causes disease'. The evidence for this variant shows: There is no evidence indicating that only loss‐of‐function variants cause disease in CBL, and the mechanism for this variant appears to be through a missense effect. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BP2 is: 'Observed in trans with a pathogenic variant for dominant disorders or in cis with a pathogenic variant'. The evidence for this variant shows: There is no data suggesting that the variant is found in trans or in cis with another pathogenic variant. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: 'In-frame deletions/insertions in a repetitive region without known function'. The evidence for this variant shows: The variant is a missense change, not an in-frame deletion or insertion. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BP4 is: 'Multiple lines of computational evidence suggest no impact'. The evidence for this variant shows: Multiple computational tools, including a high REVEL score, indicate a damaging effect. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BP5 is: 'Variant found in a case with an alternate molecular basis for disease'. The evidence for this variant shows: There is no evidence of an alternative molecular cause for the phenotype. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: 'Reputable source reports variant as benign, but without accessible evidence'. The evidence for this variant shows: The variant is reported in ClinVar as of uncertain significance rather than benign. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BP7 is: 'Synonymous variant with no predicted impact on splicing'. The evidence for this variant shows: It is a missense variant and not a synonymous change. Therefore, this criterion is not applied.