NM_000435.2:c.3278G>T

NOTCH3 · NP_000426.2:p.(Cys1093Phe) · NM_000435.2

GRCh37: chr19:15290932 C>A · GRCh38: chr19:15180121 C>A

Gene: NOTCH3 Transcript: NM_000435.2

Final call

Likely Pathogenic

PM1 moderate PM2 supporting PP2 supporting PP3 strong

Variant details

Gene

NOTCH3

Transcript

NM_000435.2

Protein

NP_000426.2:p.(Cys1093Phe)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

PM1 (Moderate): p.(Cys1093Phe) alters a cysteine in the NOTCH3 EGF-like repeat hotspot where CADASIL-causing variants cluster.

PM2 (Supporting): the variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0.

PP2 (Supporting): missense, especially cysteine-altering, variants are the established NOTCH3/CADASIL disease mechanism.

PP3 (Strong): REVEL 0.962 exceeds the >=0.932 ClinGen SVI PP3_Strong threshold.

Overall: Likely Pathogenic - one Strong + one Moderate + two Supporting meet the generic ACMG/AMP 2015 Likely Pathogenic combination.

Final determination: Generic ACMG/AMP 2015 fallback: PP3(strong) + PM1(moderate) + PM2(supporting) + PP2(supporting) satisfies the Likely Pathogenic combination (1 PS-level + 1 PM + 2 PP) and falls short of Pathogenic thresholds.

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: p.(Cys1093Phe) is a missense change, so no null-variant mechanism (nonsense-mediated decay, truncation, or splice disruption) applies.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not assessed	Not assessed: ClinVar returned no prior pathogenic classification for any other nucleotide change producing the identical amino acid change, so no comparator exists.	clinvar
PS2	Not assessed	Not assessed: no parental testing, maternity/paternity confirmation, or de novo observation was available for this variant.
PS3	Not assessed	Not assessed: no functional assay data on this variant was available, and the literature search returned zero relevant studies.
PS4	Not assessed	Not assessed: no affected-case counts, case-control enrichment, or clinical cohort evidence was available for this variant.
PM1	Met	Met (Moderate): p.(Cys1093Phe) alters a cysteine within the NOTCH3 EGF-like repeat domain, a mutation-dense hotspot where CADASIL-causing cysteine variants cluster.	pvs1_gene_context
PM2	Met	Met (Supporting): the variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, with no observed allele count or frequency.	gnomad_v2 gnomad_v4 gnomad_canada
PM3	Not assessed	Not assessed: no second pathogenic allele, phase result, or recessive-disease context was established for this variant.
PM4	N/A	Not applicable: this missense change does not alter protein length, so the in-frame insertion/deletion and stop-loss criterion does not apply.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: no prior pathogenic missense change at codon 1093 was available as a comparator.	pm5_candidates clinvar
PM6	Not assessed	Not assessed: no unconfirmed de novo observation or parental testing was provided.
PP1	Not assessed	Not assessed: no affected relatives, informative meioses, or segregation results were provided.
PP2	Met	Met (Supporting): missense variants - especially cysteine-altering changes in the EGF-like repeats - are the established NOTCH3/CADASIL disease mechanism.	pvs1_gene_context
PP3	Met	Met (Strong): REVEL score 0.962 exceeds the >=0.932 ClinGen SVI PP3_Strong calibration threshold.	revel
PP4	Not assessed	Not assessed: no patient phenotype or diagnostic features were provided to establish a highly specific presentation.
PP5	Not met	Not met: the exact variant is absent from ClinVar, with no expert-panel Pathogenic or Likely Pathogenic assertion.	clinvar
BA1	Not met	Not met: the variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, so no allele frequency reaches the stand-alone benign threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	Not met: no population allele frequency was observed in gnomAD, so the frequency is not higher than expected for the disease.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not assessed	Not assessed: no unaffected adult homozygotes or hemizygotes carrying the variant were reported.
BS3	Not assessed	Not assessed: no functional assay evidence of normal (wild-type-like) protein function was available for this variant.
BS4	Not assessed	Not assessed: no unaffected relatives tested or informative non-segregation data were provided.
BP1	Not met	Not met: missense variation is the established NOTCH3 disease mechanism, so the truncation-predominant premise of BP1 does not apply.	pvs1_gene_context
BP2	Not assessed	Not assessed: no phase, co-occurring pathogenic variant, or segregation data was available to evaluate the criterion.
BP3	N/A	Not applicable: this missense change does not alter protein length within a repetitive region.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: REVEL 0.962 strongly supports pathogenicity and no splice disruption is predicted, so no benign-leaning computational signal exists.	revel spliceai
BP5	Not assessed	Not assessed: no alternative molecular explanation for the phenotype was identified.
BP6	Not met	Not met: the exact variant is absent from ClinVar, with no expert-panel Benign or Likely Benign assertion.	clinvar
BP7	N/A	Not applicable: this missense change alters the encoded protein sequence, so the silent-variant premise of BP7 does not hold.	generic_acmg_combination_rules

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