About CUX1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
CUX1 c.2983C>T, p.(Arg995Ter)
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.
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: 3
Benign evidence criteria: 0
Pathogenic criteria applied · 3
PVS1Very strong
PVS1 · very strong
NM_001202543.1:c.2983C>T introduces a premature termination codon (p.Arg995Ter) at codon 995 of 1517 in exon 19 of 24. The premature stop is located >55 nt upstream of the last exon-exon junction (c.3921), predicting nonsense-mediated decay. Heterozygous loss-of-function variants in CUX1 are an established disease mechanism for autosomal dominant CUX1-related neurodevelopmental disorder, characterized by developmental delay, intellectual disability, hypotonia, and seizures (Oppermann et al., 2023, PMID:37644171). Under ClinGen SVI PVS1 recommendations (PMC6185798), this qualifies for PVS1 at very strong strength.
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v2.1 (0/251,110 alleles, allele frequency 0.0%) across all populations. The variant was also not detected in gnomAD v4.1, consistent with extreme rarity in the general population. This supports a pathogenic interpretation under PM2 (absent from population controls).
PP5Supporting
PP5 · supporting
This variant has been classified as Pathogenic in ClinVar (Variation ID: 4532047) by Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, a reputable clinical diagnostic laboratory (SCV007108443, criteria provided, clinical testing). The submitter cites PMID:37644171 (Oppermann et al., 2023) and PMID:25741868 (ACMG guidelines). While the general gene-level evidence is accessible, the specific clinical case details underlying the submission (individual phenotype, segregation, detailed criteria application) are not fully available for independent evaluation, satisfying the PP5 requirement that evidence from the reputable source is not fully available to the interpreting laboratory.
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, PM2 supporting, PP5 supporting; combination = 1 very strong + 2 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
This variant is present in gnomAD v2.1 (AF= 0; MAF= 0.00000%, 0/251110 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/16228 alleles, homozygotes = 0).
SpliceAI score
0.010 maximum delta
Recorded SpliceAI maximum delta score: 0.010. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
1 reported laboratory submissions
1 Pathogenic.
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
2 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV107349027, n = 2 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.
29 criteria with recorded statuses: 3 met · 17 not met · 2 not assessed · 7 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_001202543.1:c.2983C>T (p.Arg995Ter) is a nonsense variant in exon 19 of CUX1 predicted to undergo nonsense-mediated decay, meeting PVS1 at very strong strength.
The variant is absent from gnomAD v2.1 (0/251,110 alleles) and v4.1, meeting PM2 at supporting strength.
The variant has been classified as Pathogenic in ClinVar (Variation ID: 4532047) by a reputable clinical diagnostic laboratory (Victorian Clinical Genetics Services), meeting PP5 at supporting strength.
Under ACMG/AMP 2015 combination rules, one Very Strong criterion (PVS1) plus two Supporting criteria (PM2, PP5) is sufficient for a Pathogenic classification.
Heterozygous loss-of-function variants in CUX1 cause an autosomal dominant neurodevelopmental disorder characterized by global developmental delay, intellectual disability, hypotonia, and seizures, as established by Oppermann et al. (2023) in a cohort of 34 individuals.
No benign evidence was identified: the variant is too rare for BA1/BS1, no functional studies demonstrate a benign effect, and no lack of segregation or alternate molecular basis has been reported.
Final classification: Pathogenic. PVS1_VeryStrong + PM2_Supporting + PP5_Supporting.
No criteria match.
Met · 3
PVS1 Very strongNM_001202543.1:c.2983C>T introduces a premature termination codon (p.Arg995Ter) at codon 995 of 1517 in exon 19 of 24. The premature stop is located >55 nt upstream of the last exon-exon junction (c.3921), predicting nonsense-mediated decay. Heterozygous loss-of-function variants in CUX1 are an established disease mechanism for autosomal dominant CUX1-related neurodevelopmental disorder, characterized by developmental delay, intellectual disability, hypotonia, and seizures (Oppermann et al., 2023, PMID:37644171). Under ClinGen SVI PVS1 recommendations (PMC6185798), this qualifies for PVS1 at very strong strength. Details ▾Hide ▴
Evidence considered
- Nonsense variant creating premature stop codon (p.Arg995Ter) at amino acid 995 of 1517
- NMD predicted: PTC located at c.2983 in exon 19
- >55 nt upstream of last exon-exon junction at c.3921
- CUX1 haploinsufficiency is an established disease mechanism for germline neurodevelopmental disorder
- Oppermann et al. 2023: cohort of 34 individuals with heterozygous CUX1 null/missense variants presenting with global developmental delay and intellectual disability
Sources
PM2 SupportingThis variant is absent from gnomAD v2.1 (0/251,110 alleles, allele frequency 0.0%) across all populations. The variant was also not detected in gnomAD v4.1, consistent with extreme rarity in the general population. This supports a pathogenic interpretation under PM2 (absent from population controls). Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1: 0/251
- 110 alleles
- AF=0.0%
- homozygotes=0
- Absent from gnomAD v4.1
- Highest subpopulation AF: 0.0% (African/African American
- 0/16
- 228 alleles)
Sources
PP5 SupportingThis variant has been classified as Pathogenic in ClinVar (Variation ID: 4532047) by Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, a reputable clinical diagnostic laboratory (SCV007108443, criteria provided, clinical testing). The submitter cites PMID:37644171 (Oppermann et al., 2023) and PMID:25741868 (ACMG guidelines). While the general gene-level evidence is accessible, the specific clinical case details underlying the submission (individual phenotype, segregation, detailed criteria application) are not fully available for independent evaluation, satisfying the PP5 requirement that evidence from the reputable source is not fully available to the interpreting laboratory. Details ▾Hide ▴
Evidence considered
- ClinVar Variation ID 4532047: Pathogenic
- criteria provided
- single submitter
- Submitter: Victorian Clinical Genetics Services
- Murdoch Childrens Research Institute (SCV007108443)
- Submission cites PMID:37644171 and PMID:25741868
Sources
Not met · 17 · evaluated, threshold not reached
PS2 No de novo observation with confirmed maternity and paternity has been identified for this specific variant. The Oppermann et al. (2023) cohort includes de novo CUX1 variants broadly, but this specific variant was not confirmed as de novo with parentage testing in the available evidence. Details ▾Hide ▴
Still missing
- No publication or database record confirming this variant as de novo with parental confirmation
Sources
37644171
PS4 The variant has been observed in a cohort of individuals with CUX1-related neurodevelopmental disorder (Oppermann et al., 2023), but no case-control study demonstrating statistically significant enrichment in affected individuals versus population controls is available. The variant is absent from gnomAD v2.1 (0/251,110 alleles), which supports rarity but does not independently satisfy PS4 odds-ratio requirements. Details ▾Hide ▴
Evidence considered
- Variant absent from gnomAD v2.1 (0/251
- 110 alleles)
- Variant included in Oppermann et al. 2023 cohort of CUX1-related neurodevelopmental disorder cases
Still missing
- No formal case-control comparison with statistical enrichment analysis
Sources
PM1 The variant does not lie in a statistically significant mutational hotspot (Cancer Hotspots analysis: residue not significant, exact variant not listed). Although CUX1 has defined functional domains (CUT repeats, homeodomain), the variant at codon 995 is not within a recognized critical functional domain where pathogenic missense variation is enriched under PM1 criteria. Details ▾Hide ▴
Evidence considered
- Cancer Hotspots: residue not significant
- exact variant not listed
- Variant located at codon 995
- outside defined CUT DNA-binding domains and homeodomain
PM6 No publication reports this variant as assumed de novo (without confirmation of maternity/paternity). The exploratory search found no assumed de novo observations. Details ▾Hide ▴
Still missing
- No assumed de novo report for this variant
PP1 No cosegregation data are available. No family with multiple affected members carrying this variant has been reported. Details ▾Hide ▴
Still missing
- No cosegregation analysis available
PP2 PP2 applies to missense variants in genes where missense variation is a known disease mechanism and benign missense variation is rare. This variant is a nonsense (truncating) change, not a missense variant. PP2 is not applicable to null variants. Details ▾Hide ▴
No further detail was recorded.
PP3 In silico tools do not support a deleterious effect at the nucleotide level. SpliceAI predicts no significant splice impact (max delta score = 0.01). REVEL score is not available for this variant. BayesDel score is 0.60222, which is above neutral but does not reach a consensus threshold for PP3. For nonsense variants, PVS1 already captures the functional null effect, and PP3 is generally not stacked on top of PVS1 for the same underlying mechanism. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta: 0.01 (no predicted splice impact)
- BayesDel score: 0.60222
- REVEL: not found
Sources
spliceai ↗bayesdel
PP4 Insufficient phenotype specificity data are available for this specific variant. While CUX1-related neurodevelopmental disorder has a recognizable phenotype (developmental delay, intellectual disability, hypotonia, seizures), PP4 requires the individual's specific phenotype to be highly specific for the disease. The available evidence does not include detailed phenotype information for the proband carrying this variant. Details ▾Hide ▴
Evidence considered
- CUX1-related neurodevelopmental disorder phenotype includes DD/ID
- hypotonia
- seizures (Oppermann et al.
- 2023)
Still missing
- Individual-level phenotype data not available for the proband
Sources
37644171
BA1 This variant has an allele frequency of 0.0% in gnomAD v2.1 (0/251,110 alleles), well below the BA1 threshold of >1.0%. It does not meet the criterion for a common benign polymorphism. Details ▾Hide ▴
BS1 This variant has an allele frequency of 0.0% in gnomAD v2.1, well below the BS1 threshold of >0.3%. The variant is too rare to be considered a benign polymorphism based on population frequency. Details ▾Hide ▴
BS2 The variant has not been observed in a homozygous state in population controls. The CUX1-related disorder is autosomal dominant with full or high penetrance based on de novo observations in affected individuals. No healthy adult carriers of this variant have been reported, and the variant is absent from gnomAD. BS2 requires observation in a healthy adult individual for a fully penetrant dominant disorder, which is not satisfied here. Details ▾Hide ▴
Evidence considered
- Variant absent from gnomAD (0 homozygotes)
- CUX1 disorder is autosomal dominant with no reported healthy adult carriers
Sources
BS4 No evidence of lack of segregation in affected family members. BS4 requires observation that an affected family member does not carry the variant, which has not been reported. Details ▾Hide ▴
Still missing
- No segregation data available
BP1 BP1 applies to missense variants in genes where a truncating mechanism is the primary cause of disease. This variant is itself a truncating (nonsense) change, making BP1 inapplicable. A truncating variant in a gene where LOF is the disease mechanism is evidence for pathogenicity, not benignity. Details ▾Hide ▴
No further detail was recorded.
BP4 BP4 requires multiple lines of computational evidence suggesting no impact on the gene product. SpliceAI predicts no splice impact (max delta = 0.01), but this is a nonsense variant with a clear molecular consequence (premature termination, NMD). BayesDel score of 0.60222 is above neutral and does not support a benign interpretation. BP4 is generally applied to synonymous or intronic variants with no predicted splicing effect. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta: 0.01 (no splice impact predicted)
- BayesDel: 0.60222 (not clearly benign)
Sources
spliceai ↗bayesdel
BP5 BP5 applies when a variant is found in a case with an alternate molecular basis for disease. No such observation has been reported for this variant. Details ▾Hide ▴
No further detail was recorded.
BP6 BP6 requires a reputable source to classify the variant as benign or likely benign. The only ClinVar classification for this variant is Pathogenic (Variation ID: 4532047). No benign or likely benign classification from a reputable source exists. Details ▾Hide ▴
BP7 BP7 applies to synonymous variants predicted to have no impact on splicing. This variant is a nonsense (c.2983C>T, p.Arg995Ter) change, not a synonymous variant. BP7 is not applicable. Details ▾Hide ▴
No further detail was recorded.
Not assessed · 2 · no assessment recorded
PS3 No functional studies directly assessing the biological effect of NM_001202543.1:c.2983C>T were identified. The available literature (PMID:23212519, PMID:24316979) addresses CUX1 as a haploinsufficient tumor suppressor in somatic myeloid malignancies, which provides gene-level mechanistic support but does not constitute variant-specific functional evidence for germline PS3 adjudication. Details ▾Hide ▴
Evidence considered
- PMID:23212519 and PMID:24316979 establish CUX1 as a haploinsufficient tumor suppressor in somatic cancer contexts
- OncoKB classifies this variant as Likely Oncogenic/Likely Loss-of-function in somatic context
Still missing
- No germline-specific functional assay for this variant
- No published in vitro or in vivo functional characterization of p.Arg995Ter
Sources
2321251924316979
BS3 No functional studies demonstrating a benign effect for this specific variant were identified. The available cancer literature (PMID:23212519, PMID:24316979) demonstrates that CUX1 loss of function promotes tumorigenesis, which is consistent with a deleterious rather than benign effect. These studies do not provide evidence of normal protein function for this variant. No well-established in vitro or in vivo functional assay showing no deleterious impact is available for BS3 assessment. Details ▾Hide ▴
Evidence considered
- PMID:23212519 and PMID:24316979: CUX1 LOF promotes tumorigenesis (somatic cancer context)
Still missing
- No variant-specific benign functional assay available
Sources
2321251924316979
Not applicable · 7· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/APS1 applies when the same amino acid change has been established as pathogenic via a different nucleotide change. This is a nonsense variant, not a missense change amenable to PS1 evaluation. Details ▾Hide ▴
No further detail was recorded.
PM3 N/APM3 applies to recessive disorders when a variant is detected in trans with a pathogenic variant. CUX1-related neurodevelopmental disorder is autosomal dominant; PM3 is not applicable. Details ▾Hide ▴
No further detail was recorded.
PM4 N/APM4 applies to in-frame deletions/insertions or stop-loss variants. This is a single nucleotide substitution leading to a nonsense change, not an in-frame indel or stop-loss. Details ▾Hide ▴
No further detail was recorded.
PM5 N/APM5 requires identification of a pathogenic missense variant at the same amino acid residue. PM5 candidate harvesting (pm5_candidates.json) found no eligible same-residue comparator variants. Additionally, this is a nonsense variant; PM5 generally addresses novel missense changes at residues where a different pathogenic missense change has been established. Details ▾Hide ▴
No further detail was recorded.
BP2 N/ABP2 applies when a variant is observed in trans with a pathogenic variant for a fully penetrant recessive disorder. CUX1-related neurodevelopmental disorder is inherited in an autosomal dominant manner. BP2 is not applicable. Details ▾Hide ▴
No further detail was recorded.
BP3 N/ABP3 applies to in-frame deletions or insertions in repetitive regions. This variant is a single nucleotide substitution, not an in-frame indel. Details ▾Hide ▴
No further detail was recorded.
PS5 N/APS5 is not a standard ACMG/AMP 2015 criterion. Same-residue comparator analysis is addressed under PM5. PM5 candidate harvesting returned no eligible comparators (pm5_candidates.json). Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- CUX1
- Transcript
- NM_001202543.1
- Coding (HGVS c.)
- NM_001202543.1:c.2983C>T
- Protein (HGVS p.)
- NP_001189472.1:p.(Arg995Ter)
- GRCh38
- chr7:102204433 C>T
- GRCh37
- chr7:101847713 C>T
- ClinVar
- 4532047
- COSMIC
- COSV107349027
Gene diagram
Every interpreted variant in CUX1, mapped onto the exon structure of NM_001202543.1. Select a row to find it on the plot.
CUX1NM_001202543.1
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 CUX1
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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
0 / 251,110 alleles
AF 0 · 0 homozygotes
gnomAD-Canada v1.0
0 / 0 alleles
AF 0 · 0 homozygotes · FAF 0
By genetic ancestry
gnomAD v2.1
AF 0 · 0 / 251,110 alleles · 0 hom
No alternate alleles recorded in the displayed ancestry groups.
gnomAD-Canada
AF 0 · 0 / 0 alleles · 0 hom
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0; MAF= 0.00000%, 0/251110 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/16228 alleles, homozygotes = 0).
SpliceAI and Pangolin
Other predictors
- REVEL
- Not available
- BayesDel
- 0.602
How the predictions were used
PP3 In silico tools do not support a deleterious effect at the nucleotide level. SpliceAI predicts no significant splice impact (max delta score = 0.01). REVEL score is not available for this variant. BayesDel score is 0.60222, which is above neutral but does not reach a consensus threshold for PP3. For nonsense variants, PVS1 already captures the functional null effect, and PP3 is generally not stacked on top of PVS1 for the same underlying mechanism. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta: 0.01 (no predicted splice impact)
- BayesDel score: 0.60222
- REVEL: not found
Sources
spliceai ↗bayesdel
BP4 BP4 requires multiple lines of computational evidence suggesting no impact on the gene product. SpliceAI predicts no splice impact (max delta = 0.01), but this is a nonsense variant with a clear molecular consequence (premature termination, NMD). BayesDel score of 0.60222 is above neutral and does not support a benign interpretation. BP4 is generally applied to synonymous or intronic variants with no predicted splicing effect. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta: 0.01 (no splice impact predicted)
- BayesDel: 0.60222 (not clearly benign)
Sources
spliceai ↗bayesdel
BP7 BP7 applies to synonymous variants predicted to have no impact on splicing. This variant is a nonsense (c.2983C>T, p.Arg995Ter) change, not a synonymous variant. BP7 is not applicable. Details ▾Hide ▴
No further detail was recorded.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). BayesDel score = 0.60222.
4 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
-
PMID 23212519 ↗CUX1 is a haploinsufficient tumor suppressor gene on chromosome 7 frequently inactivated in acute myeloid leukemia.No paper-specific finding is recorded.
-
PMID 24316979 ↗Inactivating CUX1 mutations promote tumorigenesis.No paper-specific finding is recorded.
-
PMID 25741868 ↗Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.Richards S et al. · 2015No paper-specific finding is recorded.
-
PMID 37644171 ↗CUX1-related neurodevelopmental disorder: deep insights into phenotype-genotype spectrum and underlying pathology.Oppermann H et al. · 2023No paper-specific finding is recorded.
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 0.010
Open source ↗
ClinVar
1 Pathogenic
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/4532047/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/7-101847713-C-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr7-102204433-C-T?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001202543.1%3Ac.2…
- OncoKB ↗www.oncokb.org/gene/CUX1/R995*
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=136614143
- 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
This variant is present in gnomAD v2.1 (AF= 0; MAF= 0.00000%, 0/251110 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/16228 alleles, homozygotes = 0).
ClinVar
This variant has been reported in ClinVar as Pathogenic (1 clinical laboratory). (ClinVarID = 4532047)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). BayesDel score = 0.60222.
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 previously been reported in somatic cancers (COSMIC; COSV107349027, n = 2 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.