About NOTCH1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
NOTCH1 c.5081A>G, p.(Gln1694Arg)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
LYFE Sciences is an AI system, and it can make mistakes.
Criteria may be applied incorrectly, sources may be misread, and a
confident-looking classification can still be wrong.
Double-check every criterion and its underlying evidence
before relying on any call.
01The reasoning
How it was classified
The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 2
Benign evidence criteria: 1
Pathogenic criteria applied · 2
PM1Moderate
PM1 · moderate
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.
PM2Supporting
PM2 · supporting
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.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
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.
Recorded classification: Uncertain significance
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.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.020 maximum delta
Recorded SpliceAI maximum delta score: 0.020. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
1 reported laboratory submissions
1 Uncertain significance. ClinVar API review status: criteria provided, single submitter.
Context only
ClinVar ↗
Functional evidence
Statement recorded
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.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
1 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV99490244, n = 1 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
26 criteria with recorded statuses: 3 met · 16 not met · 3 not assessed · 4 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
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).
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).
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.
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.
No criteria match.
Met · 3
PM1 ModerateThe 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. Details ▾Hide ▴
Evidence considered
- Variant located in the NOTCH1 heterodimerization (HD) domain of the negative regulatory region
- a critical functional domain
- absent from gnomAD.
Still missing
- Domain-level constraint metrics (e.g.
- regional missense depletion scores) not directly available.
Sources
PM2 SupportingThe 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. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (exomes)
- v4.1 (exomes)
- and gnomAD-Canada v1.0 (genomes).
Sources
BP4 SupportingMultiple 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. Details ▾Hide ▴
Evidence considered
- REVEL 0.143
- BayesDel -0.403628 (add-benign)
- SpliceAI max delta 0.02.
Sources
Not met · 16 · evaluated, threshold not reached
PS2 No de novo data were identified for this variant. No publications report a confirmed de novo observation of NM_017617.5:c.5081A>G with maternity/paternity testing. Details ▾Hide ▴
Still missing
- No de novo reports available.
PS3 No variant-specific functional studies were identified for p.Gln1694Arg. OncoKB reports unknown oncogenic effect with no reviewed functional evidence. No publications with experimental functional data for this variant were found in the literature packet. Details ▾Hide ▴
Evidence considered
- OncoKB classification: Unknown Oncogenic Effect
- no variant-specific functional data identified.
Still missing
- No functional studies (in vitro or in vivo) available for this variant.
Sources
PS4 No proband counts or case-control data are available for this variant. The single ClinVar submission (Ambry Genetics, SCV006123720) does not report proband numbers. None of the ClinVar-linked publications (PMID:20301299, PMID:24882528, PMID:25173340) mention this variant in affected individuals. Details ▾Hide ▴
Evidence considered
- Single ClinVar submission (VUS) with no proband counts
- publications reviewed do not report this variant in patients.
Still missing
- No case-control or cohort data available.
Sources
PP1 No cosegregation data are available for this variant. No family studies reporting segregation of NM_017617.5:c.5081A>G with disease were identified. Details ▾Hide ▴
Still missing
- No segregation data available.
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). These in silico data do not meet the threshold for PP3. Details ▾Hide ▴
Evidence considered
- REVEL 0.143
- BayesDel -0.403628 (benign)
- SpliceAI max delta 0.02.
Sources
PP4 No specific phenotype or clinical data are available for the proband(s) carrying this variant. The single ClinVar submission does not include detailed phenotypic information for PP4 assessment. Details ▾Hide ▴
Still missing
- No proband phenotype data available.
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. None of the ClinVar-linked publications (PMID:20301299, PMID:24882528, PMID:25173340) mention this specific variant. Full-text review of PMID:24882528 confirmed the variant is entirely absent from this position statement on thoracic aortic disease management. Details ▾Hide ▴
Evidence considered
- ClinVar VUS
- single submitter (Ambry Genetics)
- no expert panel review
- linked publications do not mention this variant.
Sources
BA1 The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. Does not meet the >1% allele frequency threshold for BA1. Details ▾Hide ▴
Evidence considered
- Variant absent from all population databases.
Sources
BS1 The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. Does not meet the >0.3% allele frequency threshold for BS1. Details ▾Hide ▴
Evidence considered
- Variant absent from all population databases.
Sources
BS2 No data on observation of this variant in healthy adult controls. The variant is absent from gnomAD, providing no evidence for or against observation in healthy individuals at any age. Details ▾Hide ▴
Still missing
- No data on healthy adult carriers.
BS3 No functional studies demonstrating a neutral or benign effect were identified for this variant. While in silico predictions (REVEL 0.143, BayesDel -0.403628) suggest a tolerated/benign effect, these are computational predictions evaluated under BP4, not experimental functional evidence required for BS3. Details ▾Hide ▴
Still missing
- No experimental functional data demonstrating no deleterious effect.
BS4 No segregation data demonstrating lack of cosegregation with disease are available for this variant. Details ▾Hide ▴
Still missing
- No segregation data available.
BP1 BP1 requires a missense variant in a gene for which primarily truncating variants cause disease. In NOTCH1, both missense and truncating variants are well-established pathogenic mechanisms for germline cardiovascular disease (AOVD1, Adams-Oliver syndrome). The literature documents pathogenic missense variants across multiple functional domains (EGF repeats, NRR/HD, ANK repeats), and the disease mechanism is not predominantly limited to truncating variants. Details ▾Hide ▴
Evidence considered
- NOTCH1 germline disease involves both missense and truncating pathogenic variants
- disease is not primarily caused by truncating variants alone.
Sources
pvs1_gene_context
BP2 No observation of this variant in trans with a known pathogenic variant in NOTCH1 was reported. Details ▾Hide ▴
Still missing
- No phase data available.
BP5 No data on this variant being found in a case with an alternate molecular basis for disease. No such reports were identified in ClinVar or the literature packet. Details ▾Hide ▴
Still missing
- No alternate molecular basis data available.
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. The single submitter (Ambry Genetics) does not constitute a reputable source at expert panel level. Details ▾Hide ▴
Evidence considered
- ClinVar VUS
- single submitter
- no expert panel or multi-submitter consensus.
Sources
Not assessed · 3 · no assessment recorded
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. PS1 requires an established pathogenic comparator meeting this criterion. Details ▾Hide ▴
Still missing
- No PS1-eligible comparator variant identified in ClinVar or literature.
PM6 PM6 requires a de novo observation confirmed by maternity/paternity testing. No such data were identified for this variant in any of the reviewed sources. Details ▾Hide ▴
Still missing
- No de novo reports 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. While pathogenic NOTCH1 missense variants are well-documented, specific missense constraint metrics (e.g., gnomAD Z-score or missense oe ratio) were not available in the evidence brief for this assessment. Details ▾Hide ▴
Still missing
- Missense constraint metrics (Z-score
- oe ratio) not available for NOTCH1.
Not applicable · 4· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant (c.5081A>G, p.Gln1694Arg) and does not fall into the null-variant categories (nonsense, frameshift, or canonical ±1,2 splice consensus) defined by the ClinGen PVS1 framework (PMC6185798). The variant_bucket is 'other' and apply_generic_pvs1_framework is false. Details ▾Hide ▴
Evidence considered
- Variant is a missense substitution
- not a null variant eligible for PVS1.
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
PM5 N/ANo same-residue comparator variants (different amino acid change at position 1694 classified as pathogenic) were identified. The PM5 candidate search returned zero candidates; classic same-residue PM5 semantics could not be confirmed. Details ▾Hide ▴
Evidence considered
- Zero same-residue comparator variants identified in ClinVar.
BP7 N/ABP7 is specific to synonymous (silent) variants. NM_017617.5:c.5081A>G is a missense variant (p.Gln1694Arg) and therefore BP7 does not apply. Details ▾Hide ▴
Evidence considered
- Variant is missense
- not synonymous.
PS5 N/APS5 requires a well-established pathogenic allele identified in ClinVar at the same position. NM_017617.5:c.5081A>G is classified as Uncertain significance by a single clinical laboratory (Ambry Genetics) with review status 'criteria provided, single submitter,' which does not meet the threshold for established pathogenicity. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- NOTCH1
- Transcript
- NM_017617.5
- Coding (HGVS c.)
- NM_017617.5:c.5081A>G
- Protein (HGVS p.)
- NP_060087.3:p.(Gln1694Arg)
- GRCh38
- chr9:136503268 T>C
- GRCh37
- chr9:139397720 T>C
- ClinVar
- 3921022
- COSMIC
- COSV99490244
Gene diagram
Every interpreted variant in NOTCH1, mapped onto the exon structure of NM_017617.5. Select a row to find it on the plot.
NOTCH1NM_017617.5
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in NOTCH1
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.143
- BayesDel
- -0.404
How the predictions were used
BP4 SupportingMultiple 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. Details ▾Hide ▴
Evidence considered
- REVEL 0.143
- BayesDel -0.403628 (add-benign)
- SpliceAI max delta 0.02.
Sources
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). These in silico data do not meet the threshold for PP3. Details ▾Hide ▴
Evidence considered
- REVEL 0.143
- BayesDel -0.403628 (benign)
- SpliceAI max delta 0.02.
Sources
BP7 N/ABP7 is specific to synonymous (silent) variants. NM_017617.5:c.5081A>G is a missense variant (p.Gln1694Arg) and therefore BP7 does not apply. Details ▾Hide ▴
Evidence considered
- Variant is missense
- not synonymous.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.143. BayesDel score = -0.403628.
3 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Recorded publications
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PMID 20301299 ↗Heritable Thoracic Aortic Disease Overview.Adam MP et al. · 1993Heritable Thoracic Aortic Disease Overview (GeneReviews). Discusses thoracic aortic disease genetics at the gene level. NM_017617.5:c.5081A>G (p.Gln1694Arg) was not mentioned in the abstract or available metadata.Does not name this variant
-
PMID 24882528 ↗Canadian Cardiovascular Society position statement on the management of thoracic aortic disease.Boodhwani M et al. · 2014Canadian Cardiovascular Society position statement on the management of thoracic aortic disease. Discusses NOTCH1 in the context of bicuspid aortic valve genetics and thoracic aortic disease management. NM_017617.5:c.5081A>G was not mentioned anywhere in the full text.Does not name this variant
-
PMID 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).Erbel R et al. · 20142014 ESC Guidelines on the diagnosis and treatment of aortic diseases. A clinical practice guideline document covering thoracic aortic disease. NM_017617.5:c.5081A>G (p.Gln1694Arg) was not mentioned in the available metadata.Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
Captured gnomAD v4.1 source record
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.020
Open source ↗
ClinVar
1 Uncertain significance
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/3921022/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/9-139397720-T-C?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr9-136503268-T-C?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/9-136503268-T-C
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_017617.5%3Ac.5081…
- OncoKB ↗www.oncokb.org/gene/NOTCH1/Q1694R
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=121932006
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
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
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.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV99490244, n = 1 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.