Variant classification summary

NM_005188.4:c.1111T>C

CBL · NP_005179.2:p.(Tyr371His) · NM_005188.4

GRCh37: chr11:119148891 T>C · GRCh38: chr11:119278181 T>C

Gene: CBL Transcript: NM_005188.4

Final call

Pathogenic

PS3 strong PM2 supporting PM6 moderate PP3 strong

Variant details

Gene

CBL

Transcript

NM_005188.4

Protein

NP_005179.2:p.(Tyr371His)

gnomAD AF

2.496495544379577e-06 (v4.1)

ClinVar

Pathogenic

OncoKB

Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Pathogenic: PS3 strong was met by three independent functional studies showing abnormal disease-relevant signaling and growth.

2

Pathogenic: PP3 strong was met because REVEL 0.972 exceeds the 0.932 strong threshold.

3

Pathogenic: PM6 moderate was met because the variant was absent from both tested parents in a reported de novo case.

4

Pathogenic: PM2 supporting was met because gnomAD v4.1 frequency was far below the generic rarity threshold.

Final determination: Under the generic ACMG/AMP 2015 fallback, two strong pathogenic criteria satisfy the Pathogenic rule; PS3 strong and PP3 strong meet this requirement, with PM6 moderate and PM2 supporting also applied.

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	Not applicable: PVS1 requires a null variant (nonsense, frameshift, canonical splice, start-loss or stop-loss), and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not assessed	Not assessed: no alternate nucleotide change producing p.Tyr371His was documented, so PS1's same-amino-acid-change requirement cannot be confirmed.	clinvar PMID:28414188
PS2	Not met	Not met: the variant was absent in both parents, but confirmed maternity and paternity were not documented for the reported de novo case.	PMID:28414188
PS3	Met	Met, strong: three independent studies of p.Tyr371His demonstrated cytokine-independent growth and constitutive ERK, AKT, S6, JAK2, LYN, or STAT5 signaling.	PMID:20622007 PMID:20694012 PMID:23696637
PS4	Not assessed	Not assessed: the JMML case series lacks an exact-variant control frequency, so no OR/RR or 95% CI can be compared with the >5.0 threshold.	PMID:25741868
PM1	Not assessed	Not assessed: residue 371 lacks an authoritative critical-domain definition with documented absence of benign variation, and the hotspot search was negative.	final_classification_framework hotspots PMID:23696637
PM2	Met	Met at supporting: gnomAD v4.1 total AF is 2.50e-06 and grpmax FAF is 2.8e-07, both below the PM2 threshold of 0.0001.	gnomad_v4 gnomad_v2 PMID:28414188 PMID:25741868
PM3	N/A	Not applicable: CBL germline disease is described as dominant, while PM3 requires a recessive disorder and a pathogenic variant confirmed in trans.	PMID:20694012 PMID:28414188
PM4	N/A	Not applicable: PM4 requires a protein-length change, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: no different pathogenic missense change at Tyr371 was documented; the comparator search contained zero same-residue candidates.	pm5_candidates clinvar
PM6	Met	Met: one affected child had the variant absent from both tested parents, with de novo origin reported but maternity and paternity confirmation not documented.	PMID:28414188
PP1	Not assessed	Not assessed: no affected relatives carrying the variant or countable cosegregating meioses were reported for this family.	PMID:28414188
PP2	Not assessed	Not assessed: gene-wide benign-missense constraint and a common missense disease mechanism were not both established by the available evidence.	gnomad_v4 PMID:28414188
PP3	Met	Met, strong: REVEL 0.972 exceeds the generic PP3 strong threshold of 0.932 for this missense variant.	revel
PP4	Not assessed	Not assessed: the current patient's phenotype and family history are not supplied, so specificity for a single genetic etiology cannot be judged.	PMID:25741868
PP5	Not met	Not met: the exact variant has no ClinVar expert-panel classification, and its published evidence is available for independent evaluation.	clinvar PMID:25741868
BA1	Not met	Not met: gnomAD v4.1 grpmax FAF is 2.8e-07, far below the BA1 threshold of 0.05.	gnomad_v4 PMID:25741868
BS1	Not met	Not met: gnomAD v4.1 grpmax FAF is 2.8e-07, below the generic BS1 default threshold of 0.01.	gnomad_v4 PMID:25741868
BS2	Not assessed	Not assessed: gnomAD shows 0 homozygotes but does not document a healthy adult carrier or full early-age penetrance.	gnomad_v4 PMID:28414188 PMID:25741868
BS3	Not met	Not met: all three exact-variant functional studies reported abnormal growth or signaling, with no benign functional or splicing result for p.Tyr371His.	PMID:20622007 PMID:20694012 PMID:23696637
BS4	Not assessed	Not assessed: unaffected relatives lacked the variant, but no affected relatives were reported as non-carriers to demonstrate lack of segregation.	PMID:28414188
BP1	Not assessed	Not assessed: no comprehensive CBL disease-variant spectrum establishes that truncating variants are the primary known disease mechanism.	PMID:28414188
BP2	Not assessed	Not assessed: no pathogenic variant with documented cis/trans phase is reported, and full penetrance of the dominant CBL disorder is not established.	PMID:28414188
BP3	N/A	Not applicable: BP3 requires an in-frame indel in a repeat region, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: REVEL 0.972 is above the generic BP4 supporting threshold of 0.29, and SpliceAI is not applicable to this missense path.	revel
BP5	Not assessed	Not assessed: no complete current-case molecular workup is available to determine whether an alternate pathogenic basis for disease exists.	PMID:25741868
BP6	Not met	Not met: no exact-variant benign expert-panel classification is present; ClinVar contains only pathogenic or likely pathogenic laboratory assertions.	clinvar PMID:25741868
BP7	N/A	Not applicable: BP7 requires a synonymous variant, and this is a missense variant.	generic_acmg_combination_rules

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