NM_017617.5:c.5081A>G (p.Gln1694Arg) is a missense variant in the NOTCH1 gene encoding the notch receptor 1. The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases (PM2_supporting).1 The variant lies within the heterodimerization (HD) domain of the NOTCH1 negative regulatory region (NRR), a well-characterized functional domain critical for maintaining receptor autoinhibition. Pathogenic missense variants in this domain are established in both germline cardiovascular disease and somatic cancers (PM1). Multiple lines of computational evidence suggest no deleterious effect: REVEL score 0.143, BayesDel score -0.403628, and SpliceAI max delta 0.02 (BP4).2 ClinVar classifies this variant as Uncertain significance with a single submitter (Ambry Genetics); no expert panel review is available, and the linked publications do not mention this specific variant.3 No functional studies (PS3/BS3), segregation data (PP1/BS4), de novo observations (PS2/PM6), or case-control data (PS4) are available for this variant. Applying generic ACMG/AMP 2015 combination rules: 1 moderate pathogenic (PM1) + 1 supporting pathogenic (PM2_supporting) versus 1 supporting benign (BP4) is consistent with a classification of Uncertain Significance.4
NOTCH1
Final classification
VUS
NOTCH1 c.5081A>G · p.Gln1694Arg
NOTCH1
NM_017617.5:c.5081A>G (p.Gln1694Arg) is a missense variant in the NOTCH1 gene encoding the notch receptor 1.
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, BP4 supporting; combination = 1 moderate + 1 supporting + 1 supporting benign, which maps to VUS.
Classification rationale
PM1PM2
BP4
VUS
NOTCH1 c.5081A>G
PM1 + PM2 + BP4
→
VUS
2
revelbayesdelspliceai ↗
4
generic_acmg_combination_rules
Gene diagram
· NM_017617.5 · variants mapped to exon structure
NOTCH1
NM_017617.5
Fetching transcript structure from UCSC…
Applied criteria · 3 applied · 19 assessed
Applied · 3
Strength
Supporting
Moderate
Strong
Very strong
✓
PM1
moderate
Pathogenic
The variant p.Gln1694Arg lies within the heterodimerization (HD) domain of the NOTCH1 negative regulatory region (NRR), a well-characterized functional domain critical for maintaining the autoinhibitory conformation of the receptor. Missense mutations in the NRR/HD domain are established as pathogenic in both germline cardiovascular disease (Adams-Oliver syndrome, aortic valve disease 1) and somatic cancers (T-ALL). The variant is absent from gnomAD population databases, consistent with lack of benign variation in this domain.
Variant located in the NOTCH1 heterodimerization (HD) domain of the negative regulatory regiona critical functional domainabsent from gnomAD.
✓
PM2
supporting
Pathogenic
The variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada, meeting the allele frequency threshold of <0.1% for PM2 at supporting strength.
Absent from gnomAD v2.1 (exomes)v4.1 (exomes)and gnomAD-Canada v1.0 (genomes).
✓
BP4
supporting
Benign
Multiple lines of computational evidence suggest no impact on gene product: REVEL score 0.143 (below the 0.5 threshold), BayesDel score -0.403628 (negative/add-benign prediction), and SpliceAI max delta score 0.02 (no predicted splice alteration). These concordant in silico predictions support a benign effect.
REVEL 0.143BayesDel -0.403628 (add-benign)SpliceAI max delta 0.02.
Assessed · not applied
Pathogenic
PS1
No comparator variant with a different nucleotide change at the same codon producing the same amino acid change (p.Gln1694Arg) was identified in the case materials.
PS2
No de novo data were identified for this variant.
PS3
No variant-specific functional studies were identified for p.Gln1694Arg.
PS4
No proband counts or case-control data are available for this variant.
PM6
PM6 requires a de novo observation confirmed by maternity/paternity testing.
PP1
No cosegregation data are available for this variant.
PP2
PP2 requires the variant to be a missense change in a gene with a low rate of benign missense variation and where missense variants are a common mechanism of disease.
PP3
Multiple lines of computational evidence do not support a deleterious effect: REVEL score 0.143 (well below the 0.5 threshold), BayesDel score -0.403628 (negative/add-benign prediction), and SpliceAI max delta score 0.02 (no predicted splice impact).
PP4
No specific phenotype or clinical data are available for the proband(s) carrying this variant.
PP5
ClinVar classification is Uncertain significance with review status 'criteria provided, single submitter.' The 3-star expert panel review threshold required for PP5 at supporting strength is not met.
Benign
BA1
The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada.
BS1
The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada.
BS2
No data on observation of this variant in healthy adult controls.
BS3
No functional studies demonstrating a neutral or benign effect were identified for this variant.
BS4
No segregation data demonstrating lack of cosegregation with disease are available for this variant.
BP1
BP1 requires a missense variant in a gene for which primarily truncating variants cause disease.
BP2
No observation of this variant in trans with a known pathogenic variant in NOTCH1 was reported.
BP5
No data on this variant being found in a case with an alternate molecular basis for disease.
BP6
ClinVar classification is Uncertain significance with review status 'criteria provided, single submitter.' The 3-star expert panel review threshold required for BP6 at supporting strength is not met.
N/A · 3
PVS1 · PM5 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
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 = 3921022)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.143. BayesDel score = -0.403628.
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. NOTCH1, a transmembrane receptor and transcription factor, can function as both an oncogene and tumor suppressor.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV99490244, n = 1 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
Triaged references · 3 PMIDs not cited in assessment
24882528 ↗
Canadian Cardiovascular Society position statement on the management of thoracic aortic disease.
CLINVAR
25173340 ↗
2014 ESC Guidelines on the diagnosis and treatment of aortic diseases: Document covering acute and chronic aortic diseases of the thoracic and abdominal aorta of the adult. The Task Force for the Diagnosis and Treatment of Aortic Diseases of the European Society of Cardiology (ESC).
CLINVAR