NM_005188.3:c.1147A>C

CBL · NP_005179.2:p.(Ile383Leu) · NM_005188.3

GRCh37: chr11:119148927 A>C · GRCh38: chr11:119278217 A>C

Gene: CBL Transcript: NM_005188.3

Final call

VUS

PM1 moderate PM2 supporting PP3 supporting

Variant details

Gene

CBL

Transcript

NM_005188.3

Protein

NP_005179.2:p.(Ile383Leu)

gnomAD AF

6.203212271442644e-07 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

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).

This variant has been reported in ClinVar as Uncertain significance by a single clinical laboratory (Labcorp/Invitae, SCV002596392). No expert panel review is available.

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.

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).

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	PVS1 is not applicable to this missense variant (p.Ile383Leu). The variant does not fall into the default generic PVS1 null-variant buckets of nonsense, frameshift, or canonical +/-1,2 splice consensus variants, and no evidence of aberrant splicing leading to nonsense-mediated decay has been identified (SpliceAI max delta = 0.00).	pvs1_generic_framework pvs1_variant_assessment spliceai
PS1	Not assessed	No evidence of a different nucleotide change at codon 383 (c.1147) predicting the same missense change (p.Ile383Leu) with an established pathogenic classification. No such variant was identified in ClinVar or the literature.	clinvar
PS2	Not met	No de novo occurrence of NM_005188.3:c.1147A>C has been reported in the literature or in ClinVar. Exploratory literature search found no studies documenting de novo status for this variant.	clinvar
PS3	Not met	No well-established functional studies demonstrate a damaging effect for this exact variant. OncoKB classifies this variant as 'Unknown Oncogenic Effect.' The variant resides in the CBL RING finger domain, a known functional domain, but direct experimental evidence (e.g., ubiquitin ligase activity, signaling assays) for p.Ile383Leu is absent from the literature.	oncokb
PS4	Not met	No case-control data or statistically significant enrichment in affected individuals versus controls is available. The variant is present in only 1 of 251,292 alleles in gnomAD v2.1 and 1 of 1,612,068 alleles in gnomAD v4.1. A single ClinVar submission (Labcorp/Invitae) classifies it as Uncertain significance without aggregate case counts. The variant prevalence in affected populations is not established.	gnomad_v2 gnomad_v4 clinvar
PS5	Not assessed	PS5 requires a novel missense change at an amino acid residue where a different pathogenic missense change has been previously observed. No pathogenic missense variant at residue 383 was identified in the evidence set. PM5 candidate harvesting found zero same-residue comparator variants.	pm5_candidates
PM1	Met	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.	pvs1_gene_context
PM2	Met	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 gnomad_v4
PM5	Not assessed	PM5 candidate harvesting found no same-residue comparator variants for residue 383. No different missense change at this residue with an established pathogenic classification was identified in ClinVar or the literature.	pm5_candidates clinvar
PM6	Not met	No assumed de novo observations have been reported for this variant. Exploratory literature search found no cases of de novo occurrence without confirmed parentage. PM6 cannot be applied without at least one reported de novo event.
PP1	Not met	No segregation data are available for this variant. No family studies demonstrating cosegregation of NM_005188.3:c.1147A>C with disease in multiple affected family members have been published.
PP2	Not assessed	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. While CBL-related disorders are indeed caused by missense variants (gain-of-function mechanism in the RING domain), gene-level constraint metrics (e.g., missense Z-score, o/e ratio) are not available in the evidence set to assess the rate of benign missense variation.
PP3	Met	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 bayesdel spliceai
PP4	Not assessed	PP4 requires the patient's phenotype or family history to be highly specific for a disease with a single genetic etiology. No patient-specific phenotype information is available for this case.
PP5	Not met	No reputable source reports this variant as pathogenic. The sole ClinVar submission (Labcorp/Invitae, SCV002596392) classifies it as Uncertain significance. The only PMID cited by that submission (28492532) is a methodology paper describing the Sherloc classification framework and does not mention this specific variant. No other source asserts pathogenicity.	clinvar
BA1	Not met	BA1 requires an allele frequency >1% in population databases. This variant has an allele frequency of 3.98x10^-6 in gnomAD v2.1 and 6.20x10^-7 in gnomAD v4.1, both far below the 1% threshold.	gnomad_v2 gnomad_v4
BS1	Not met	BS1 requires an allele frequency >0.3% in population databases. This variant is observed at 3.98x10^-6 (v2.1) and 6.20x10^-7 (v4.1), far below the 0.3% threshold.	gnomad_v2 gnomad_v4
BS2	Not assessed	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. CBL-related disorders (Noonan-like syndrome/CBL syndrome) can exhibit variable expressivity and incomplete penetrance, so observation in a population database does not exclude pathogenicity. Without phenotype confirmation, BS2 cannot be reliably applied.	gnomad_v2 gnomad_v4
BS3	Not met	No well-established functional studies demonstrate a neutral or benign effect for this variant. Exploratory search found no in vitro or in vivo functional assays showing no damaging effect for p.Ile383Leu.	oncokb
BS4	Not met	BS4 requires lack of segregation in affected family members. No family segregation data are available for this variant.
BP1	N/A	BP1 applies when a missense variant occurs in a gene for which primarily truncating variants cause disease. CBL-related disorders are primarily caused by gain-of-function missense variants in the RING finger and linker domains, not by truncating loss-of-function variants. Therefore BP1 does not apply.	pvs1_gene_context
BP2	N/A	BP2 applies when a variant is observed in trans with a pathogenic variant in a recessive disorder. CBL-related disorders are autosomal dominant (Noonan-like syndrome/CBL syndrome), not recessive. BP2 is not applicable.	pvs1_gene_context
BP4	Not met	BP4 requires multiple lines of computational evidence suggesting no impact. REVEL strongly predicts a deleterious effect (0.786), which contradicts benign interpretation. Although BayesDel (0.134) and SpliceAI (0.00) are neutral, the REVEL score alone precludes application of BP4.	revel bayesdel spliceai
BP5	Not met	BP5 requires the variant to be found in a case with an alternate molecular basis for disease. No such evidence is available for this variant.
BP6	Not met	No reputable source reports this variant as benign. The sole ClinVar submission classifies it as Uncertain significance. No expert panel or clinical laboratory has asserted a benign classification.	clinvar
BP7	N/A	BP7 applies to synonymous (silent) variants with no predicted splice impact. NM_005188.3:c.1147A>C is a missense variant (p.Ile383Leu), not synonymous.

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