NOTCH3c.5032G>TPathogenic

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Variant interpretation report

NOTCH3 c.5032G>T, p.(Glu1678Ter)

NM_000435.2:c.5032G>T NP_000426.2:p.(Glu1678Ter) View identifiers

Classification

Pathogenic

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is pathogenic. Select a step to read what it means.

Pathogenic.A pathogenic classification under the recorded framework.

In plain language

Gene-level background from the recorded interpretation.

About NOTCH3

No gene-level summary was recorded for this case.

Key facts

Evidence used: 1 very strong (pathogenic) · 1 moderate (pathogenic) · 1 supporting (pathogenic)
Expert rules: Not recorded
Pipeline record: 29 Jul 2026 · version 7.0.4

Evidence considered

View criteria

Applied evidence criteria

PVS1 (very strong): Nonsense variant NM_000435.2:c.5032G>T (p.Glu1678Ter) in exon 27 of 33 introduces a premature termination codon predicted to trigger nonsense-mediated decay or produce a truncated protein lacking the C-terminal 644 amino acids including the ANK repeat and PEST domains. NOTCH3 loss-of-function is established as a germline disease mechanism by recent literature demonstrating recessive LoF variants cause early-onset arteriopathy and trans LoF variants modify CADASIL severity. Assessed under ClinGen SVI PVS1 framework (PMC6185798).
PM1 (moderate): The nonsense variant at p.Glu1678Ter is located in the NOTCH3 intracellular domain and truncates the protein, removing the ankyrin repeat domain and the PEST degradation domain — both well-characterized functional regions essential for NOTCH3 transcriptional activity and protein turnover. The truncated ICD is critical for Notch signaling, consistent with PM1 domain-level application.
PM2 (supporting): NM_000435.2:c.5032G>T is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, with an allele frequency of 0 in all population databases. This is well below the PM2 threshold of <0.1% for non-VCEP frameworks.

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: 3 Benign evidence criteria: 0

Pathogenic criteria applied · 3

PVS1Very strong

PVS1 · very strong

Nonsense variant NM_000435.2:c.5032G>T (p.Glu1678Ter) in exon 27 of 33 introduces a premature termination codon predicted to trigger nonsense-mediated decay or produce a truncated protein lacking the C-terminal 644 amino acids including the ANK repeat and PEST domains. NOTCH3 loss-of-function is established as a germline disease mechanism by recent literature demonstrating recessive LoF variants cause early-onset arteriopathy and trans LoF variants modify CADASIL severity. Assessed under ClinGen SVI PVS1 framework (PMC6185798).

PM1Moderate

PM1 · moderate

The nonsense variant at p.Glu1678Ter is located in the NOTCH3 intracellular domain and truncates the protein, removing the ankyrin repeat domain and the PEST degradation domain — both well-characterized functional regions essential for NOTCH3 transcriptional activity and protein turnover. The truncated ICD is critical for Notch signaling, consistent with PM1 domain-level application.

PM2Supporting

PM2 · supporting

NM_000435.2:c.5032G>T is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, with an allele frequency of 0 in all population databases. This is well below the PM2 threshold of <0.1% for non-VCEP frameworks.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Pathogenic

gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PVS1 very strong, PM1 moderate, PM2 supporting; combination = 1 very strong + 1 moderate + 1 supporting, which maps to Pathogenic.

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.

Applied · PM2 →

gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗

SpliceAI score

0.160 maximum delta

Recorded SpliceAI maximum delta score: 0.160. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied SpliceAI ↗

ClinVar submissions

Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗

Functional evidence

Statement recorded

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.

No listed criterion applied OncoKB ↗

COSMIC

Cancer Hotspots

Somatic evidence

No matching record reported

This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only

COSMIC ↗Cancer Hotspots ↗

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 · 17 not met · 0 not assessed · 6 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic

PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM5 PM6 PP1 PP2 PP3 PP4 PP5 PS5

Benign

BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP4 BP5 BP6 BP7

Met Not met Not assessed Not applicable

PVS1 (very strong): NM_000435.2:c.5032G>T is a nonsense variant in exon 27 of 33, predicted to produce a premature termination codon at p.Glu1678Ter and trigger nonsense-mediated decay. NOTCH3 loss-of-function is established as a germline disease mechanism, satisfying PVS1 at very strong level under the ClinGen SVI PVS1 framework (PMC6185798).

PM1 (moderate): The nonsense variant truncates the NOTCH3 intracellular domain, removing the ankyrin repeat domain essential for transcriptional activation and the PEST domain that regulates protein stability. These are well-characterized, functionally critical domains.

PM2 (supporting): The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada (AF=0), meeting the PM2 threshold of <0.1% allele frequency in population databases.

Met · 3

PVS1 Very strongNonsense variant NM_000435.2:c.5032G>T (p.Glu1678Ter) in exon 27 of 33 introduces a premature termination codon predicted to trigger nonsense-mediated decay or produce a truncated protein lacking the C-terminal 644 amino acids including the ANK repeat and PEST domains. NOTCH3 loss-of-function is established as a germline disease mechanism by recent literature demonstrating recessive LoF variants cause early-onset arteriopathy and trans LoF variants modify CADASIL severity. Assessed under ClinGen SVI PVS1 framework (PMC6185798). Details ▾Hide ▴

Evidence considered

Nonsense variant at c.5032 (exon 27/33) predicted to trigger NMD
NOTCH3 LoF mechanism supported by germline disease literature (PMID:41196431
PMID:41947304)
PVS1 weight table for nonsense variants under PMC6185798 assigns PVS1 (very strong) when LoF is an established mechanism

Sources

pvs1_generic_framework ↗pvs1_gene_contextpvs1_variant_assessment

PM1 ModerateThe nonsense variant at p.Glu1678Ter is located in the NOTCH3 intracellular domain and truncates the protein, removing the ankyrin repeat domain and the PEST degradation domain — both well-characterized functional regions essential for NOTCH3 transcriptional activity and protein turnover. The truncated ICD is critical for Notch signaling, consistent with PM1 domain-level application. Details ▾Hide ▴

Evidence considered

Truncation removes ANK repeat domain and PEST domain in the NOTCH3 ICD
ANK repeats required for transcriptional activation
PEST domain regulates protein stability
PMID:19825845 describes the functional consequence of mutant Notch3 retention and toxicity
supporting ICD functional importance

Sources

PMID:19825845 ↗

PM2 SupportingNM_000435.2:c.5032G>T is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, with an allele frequency of 0 in all population databases. This is well below the PM2 threshold of <0.1% for non-VCEP frameworks. Details ▾Hide ▴

Evidence considered

Absent from gnomAD v2.1 (AF = 0)
Absent from gnomAD v4.1 (AF = 0)
Absent from gnomAD-Canada v1.0 (AF = 0)

Sources

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

Not met · 17 · evaluated, threshold not reached

PS2 No de novo observation was identified for NM_000435.2:c.5032G>T in any source. The variant is absent from ClinVar and the reviewed literature. Details ▾Hide ▴

Still missing

No de novo testing data available

PS3 No variant-specific functional data exists for NM_000435.2:c.5032G>T. The two publications reviewed (PMID:19825845, PMID:25870235) do not test or mention this variant. No systematic range characterization encompassing position 1678 was identified. Details ▾Hide ▴

Evidence considered

PMID:19825845 assessed NOTCH3 p.R133C and p.C185R only — variant not tested
PMID:25870235 assessed NOTCH3 p.R103X null allele — variant not tested

Still missing

No functional studies of p.Glu1678Ter available

PS4 The variant has not been reported in affected individuals. It is absent from ClinVar and was not identified in any case report or cohort study in the reviewed literature. No case-control data are available. Details ▾Hide ▴

Evidence considered

Absent from ClinVar and all population databases

Still missing

No patient observations available

Sources

clinvar ↗

PM5 No pathogenic missense variant at codon 1678 was identified. The PM5 candidate search returned no comparators for same-residue analysis. PM5 requires a different pathogenic amino acid change at the same residue, which was not found. Details ▾Hide ▴

Evidence considered

No ClinVar pathogenic/likely pathogenic variant at codon 1678

Sources

pm5_candidates

PM6 No de novo observation was identified for NM_000435.2:c.5032G>T. The variant is absent from ClinVar and the reviewed literature provides no de novo data. Details ▾Hide ▴

Still missing

No de novo testing or parental data available

PP1 No segregation data are available for this variant. Neither ClinVar nor the reviewed literature provides cosegregation information. Details ▾Hide ▴

Still missing

No family segregation data available

PP3 BayesDel score of 0.66 is consistent with a deleterious prediction, but in silico pathogenicity predictors are calibrated for missense variants and are not validated for nonsense variants. Applying PP3 would double-count the evidence already captured by PVS1. SpliceAI predicts no splice impact (max delta 0.16). REVEL score is unavailable. Details ▾Hide ▴

Evidence considered

BayesDel score 0.66 (deleterious direction)
SpliceAI max delta 0.16 (no splice impact)
REVEL not available

Sources

bayesdelspliceai ↗

PP4 No patient phenotype or family history data were submitted with this variant. PP4 requires the patient's phenotype to be specific for and consistent with the gene's disease spectrum. Details ▾Hide ▴

Still missing

No patient phenotype data provided

PP5 NM_000435.2:c.5032G>T is absent from ClinVar. No expert panel or reputable source has classified this variant as pathogenic. Details ▾Hide ▴

Evidence considered

Variant not present in ClinVar

Sources

clinvar ↗

BA1 The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada (AF=0). BA1 requires an allele frequency greater than 1% in any population database. Details ▾Hide ▴

Evidence considered

AF = 0 across all population databases

Sources

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

BS1 The variant is absent from all population databases (AF=0). BS1 requires an allele frequency greater than 0.3% for a dominant disorder. Details ▾Hide ▴

Evidence considered

AF = 0 across all population databases

Sources

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

BS2 The variant is absent from gnomAD; no homozygous observations exist in healthy adults. For a fully penetrant dominant disorder like CADASIL, BS2 requires observation of the variant in healthy adult controls or in a homozygous state in population databases. Details ▾Hide ▴

Evidence considered

No healthy adult observations
variant absent from gnomAD

Sources

gnomad_v2 ↗gnomad_v4 ↗

BS3 No functional data demonstrating a neutral or benign effect for NM_000435.2:c.5032G>T were identified. The reviewed publications do not test this variant. Details ▾Hide ▴

Still missing

No functional studies of this variant available

BS4 No segregation data are available to assess lack of cosegregation with disease. The variant has not been reported in any family study. Details ▾Hide ▴

Still missing

No family segregation data available

BP2 No observation of this variant in trans with a pathogenic NOTCH3 variant or in cis with a pathogenic variant in any inheritance pattern was identified. Details ▾Hide ▴

Still missing

No phase data available

BP5 No alternative molecular basis for disease was identified because no patient case data with a different causative variant were available for comparison. Details ▾Hide ▴

Still missing

No patient case data with alternative molecular diagnosis

BP6 NM_000435.2:c.5032G>T is absent from ClinVar. No trusted source has reported this variant as benign. BP6 requires a reputable source classification as benign. Details ▾Hide ▴

Evidence considered

Variant not present in ClinVar

Sources

clinvar ↗

Not applicable · 6· recorded as not applicable Show reasons ▾Hide reasons ▴

PS1 N/APS1 applies to missense variants where a different nucleotide change produces the same amino acid substitution; not applicable to nonsense variants. Details ▾Hide ▴

No further detail was recorded.

PP2 N/APP2 applies to missense variants in genes with a low rate of benign missense variation and where missense variants are a common disease mechanism. This is a nonsense variant. Details ▾Hide ▴

No further detail was recorded.

BP1 N/ABP1 applies to missense variants in genes where only truncating variants are known to cause disease. This is a nonsense (truncating) variant, and NOTCH3 CADASIL is primarily caused by missense variants. Details ▾Hide ▴

No further detail was recorded.

BP4 N/ABP4 applies to computational evidence suggesting no impact on gene product for missense and splice variants. In silico predictors are not calibrated for nonsense variants; applying BP4 to a stop-gain is not meaningful. BayesDel score 0.66 does not support a benign effect. Details ▾Hide ▴

No further detail was recorded.

BP7 N/ABP7 applies to synonymous variants at non-conserved positions where splice prediction algorithms predict no impact. This is a nonsense variant. Details ▾Hide ▴

No further detail was recorded.

PS5 N/APS5 requires a variant detected in trans with a pathogenic variant for a recessive disorder. CADASIL is autosomal dominant; PS5 does not apply. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene: NOTCH3
Transcript: NM_000435.2
Coding (HGVS c.): NM_000435.2:c.5032G>T
Protein (HGVS p.): NP_000426.2:p.(Glu1678Ter)
GRCh38: chr19:15170413 C>A
GRCh37: chr19:15281224 C>A

Gene diagram

Every interpreted variant in NOTCH3, mapped onto the exon structure of NM_000435.2. Select a row to find it on the plot.

NOTCH3NM_000435.2

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 NOTCH3 — 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

SpliceAI acceptor lossat +140 bp

0.070

SpliceAI acceptor gainat -3 bp

0.160

SpliceAI donor lossat -82 bp

0.100

SpliceAI donor gainat +67 bp

0.000

Pangolin splice lossmagnitude shown

-0.210

Pangolin splice gain

0.130

Other predictors

REVEL: Not available
BayesDel: 0.660

How the predictions were used

Evidence considered

BayesDel score 0.66 (deleterious direction)
SpliceAI max delta 0.16 (no splice impact)
REVEL not available

Sources

bayesdelspliceai ↗

No further detail was recorded.

BP7 N/ABP7 applies to synonymous variants at non-conserved positions where splice prediction algorithms predict no impact. This is a nonsense variant. Details ▾Hide ▴

No further detail was recorded.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.16). BayesDel score = 0.66.

2 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

Mutations in NOTCH3 cause the formation and retention of aggregates in the endoplasmic reticulum, leading to impaired cell proliferation.

Investigated cytotoxic properties of NOTCH3 mutants p.R133C and p.C185R in stable HEK293 cell lines. Both mutants formed ER-retained aggregates resistant to degradation, impairing cell proliferation and increasing proteasome inhibition sensitivity. NM_000435.2:c.5032G>T (p.Glu1678Ter) was not studied or mentioned.
Does not name this variant
PMID 19825845 ↗
Homozygous NOTCH3 null mutation and impaired NOTCH3 signaling in recessive early-onset arteriopathy and cavitating leukoencephalopathy.

Reported a homozygous NOTCH3 null mutation (p.R103X) causing recessive early-onset arteriopathy and cavitating leukoencephalopathy, demonstrating that complete NOTCH3 loss-of-function can cause a severe cerebrovascular phenotype distinct from classic CADASIL. NM_000435.2:c.5032G>T (p.Glu1678Ter) was not studied or mentioned.
Does not name this variant
PMID 25870235 ↗

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 0.160 Open source ↗

ClinVar Captured ClinVar source record 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

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 is absent from ClinVar.

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.16). BayesDel score = 0.66.

Functional

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.

Somatic

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.