CUX1 c.652dup, p.Thr218AsnfsTer7
NM_001202543.1:c.652dup
Pathogenic
NM_001202543.1:c.652dupA (T218Nfs*7) is a loss-of-function frameshift variant in CUX1, a gene with established haploinsufficient disease mechanism. It is absent from population databases (PM2), supported by well-established functional studies demonstrating damaging effects (PS3), and qualifies as a null variant under PVS1. Computational data suggest no splicing impact (BP4). The combination of PVS1, PS3, and PM2 supports a Pathogenic classification.
ACMG/AMP Criteria Applied
PVS1
PS3
PM2
BP4
Genetic Information
Gene & Transcript Details
Gene
CUX1
Transcript
NM_001202543.1
Total Exons
24
Strand
Forward (+)
Reference Sequence
NC_000007.13
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_001202543.2 | Alternative | 24 exons | Forward |
Variant Details
HGVS Notation
NM_001202543.1:c.652dup
Protein Change
T218Nfs*7
Location
Exon 8
(Exon 8 of 24)
5'Exon Structure (24 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 218 in gene CUX1
Variant interpretation based on transcript NM_001202543.1
Genome Browser
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HGVS InputNM_001202543:c.652dup
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Population Frequency
Global Frequency
0.0 in 100,000
Extremely Rare
Global: 0.0%
0%
0.05%
0.1%
1%
5%
10%+
ACMG Criteria Applied
PM2
This variant is not present in gnomAD (PM2 criteria applies).
Classification
Unknown
Publications (0)
No publication details.
Clinical Statement
Functional Impact
Functional Domain
Hotspot Status
Not a hotspot
Domain Summary
This variant is not located in a mutational hotspot or critical domain (0 mutations).
Related Variants in This Domain
No evidence of other pathogenic variants at position 218 in gene CUX1
Functional Summary
The CUX1 T218Nfs*7 variant is a truncating mutation in the CUX1 gene, which functions as a haploinsufficient tumor suppressor. Functional evidence indicates that truncating mutations in CUX1 lead to reduced protein expression, activation of the PI3K signaling pathway, and tumor growth. This variant is therefore likely to have a damaging effect.
Database Previews
OncoKB
JAX-CKB
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Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Unknown
PP3 Applied
No
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1
PVS1 (Very Strong)
According to standard ACMG guidelines, the rule for PVS1 is: 'Null variant in a gene where loss of function is a known mechanism of disease (e.g., nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single exon deletion in a LoF gene)'. The evidence shows: NM_001202543.1:c.652dupA is a frameshift variant predicted to introduce a premature stop codon (T218Nfs*7) not in the last exon, likely leading to nonsense-mediated decay. Therefore, PVS1 is applied at Very Strong strength because the variant is a null variant in a gene where loss of function is the established disease mechanism.
PS1
PS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS1 is: 'Same amino acid change as a known pathogenic variant but different nucleotide change'. The evidence shows: no known pathogenic variant causes the same amino acid change T218Nfs*7 by a different nucleotide change. Therefore, PS1 is not applied because the criterion is not met.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS2 is: 'De novo (both maternity and paternity confirmed) in a patient with the disease and no family history'. The evidence shows: de novo status has not been assessed; parental testing data are unavailable. Therefore, PS2 is not applied because evidence of a confirmed de novo occurrence is not available.
PS3
PS3 (Strong)
According to standard ACMG guidelines, the rule for PS3 is: 'Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product'. The evidence shows: functional studies demonstrate that CUX1 truncating mutations reduce protein expression, activate the PI3K signaling pathway, and promote tumor growth. Therefore, PS3 is applied at Strong strength because well-established functional data support a damaging effect.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS4 is: 'Prevalence of the variant in affected individuals is significantly increased compared with controls'. The evidence shows: there are no case-control or cohort data for NM_001202543.1:c.652dupA. Therefore, PS4 is not applied because prevalence data in affected individuals are lacking.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM1 is: 'Located in a mutational hot spot or well-established functional domain without benign variation'. The evidence shows: this variant is a frameshift and is not located in a defined mutational hotspot or known functional domain. Therefore, PM1 is not applied because it does not meet hotspot/domain criteria.
PM2
PM2 (Moderate)
According to standard ACMG guidelines, the rule for PM2 is: 'Absent from controls (or at extremely low frequency if recessive)'. The evidence shows: NM_001202543.1:c.652dupA is not present in population databases including gnomAD. Therefore, PM2 is applied at Moderate strength because the variant is absent from controls.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM3 is: 'Detected in trans with a pathogenic variant for recessive disorders'. The evidence shows: CUX1-related disease is autosomal dominant due to haploinsufficiency, and trans data are not relevant. Therefore, PM3 is not applied because the inheritance and data do not support this criterion.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM4 is: 'Protein length changes due to in-frame deletions/insertions or stop-loss variants'. The evidence shows: the variant causes a frameshift with premature truncation, not an in-frame change. Therefore, PM4 is not applied because it is not an in-frame indel or stop-loss.
PM5
PM5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM5 is: 'Novel missense change at an amino acid residue where a different pathogenic missense change has been seen'. The evidence shows: this is a frameshift variant, not missense, and no missense variants at this residue are reported. Therefore, PM5 is not applied because the variant is not missense.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM6 is: 'Assumed de novo, but without confirmation of paternity and maternity'. The evidence shows: no data on de novo occurrence without parental confirmation. Therefore, PM6 is not applied because there is no evidence of an assumed de novo event.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP1 is: 'Co-segregation with disease in multiple affected family members'. The evidence shows: no family segregation data are available. Therefore, PP1 is not applied because segregation information is lacking.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP2 is: 'Missense variant in a gene with a low rate of benign missense variation and where missense variants are a common mechanism of disease'. The evidence shows: the variant is a frameshift, not missense. Therefore, PP2 is not applied because it is not applicable to this variant type.
PP3
PP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP3 is: 'Multiple lines of computational evidence support a deleterious effect'. The evidence shows: in silico tools including SpliceAI predict minimal impact on splicing (score 0.01) and no deleterious effect. Therefore, PP3 is not applied because computational evidence does not support a damaging impact.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: 'Patient's phenotype or family history highly specific for a disease with a single genetic etiology'. The evidence shows: no phenotype or clinical data are provided. Therefore, PP4 is not applied because phenotype specificity data are lacking.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: 'Reputable source reports variant as pathogenic, but without accessible evidence'. The evidence shows: the variant is not reported in ClinVar or other reputable sources. Therefore, PP5 is not applied because no such reports exist.
BA1
BA1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BA1 is: 'Allele frequency is too high for the disorder'. The evidence shows: the variant is absent from population databases. Therefore, BA1 is not applied because allele frequency is not above the high-frequency threshold.
BS1
BS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS1 is: 'Allele frequency is greater than expected for the disorder'. The evidence shows: the variant is absent from controls. Therefore, BS1 is not applied because allele frequency is not greater than expected.
BS2
BS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS2 is: 'Observed in healthy individuals with full penetrance expected at an early age'. The evidence shows: no observations in healthy individuals are documented. Therefore, BS2 is not applied because such data are absent.
BS3
BS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS3 is: 'Well-established functional studies show no damaging effect on protein function or splicing'. The evidence shows: functional studies demonstrate damaging effects of truncating CUX1 variants. Therefore, BS3 is not applied because functional data indicate a damaging effect.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS4 is: 'Lack of segregation in affected family members'. The evidence shows: no segregation data are available. Therefore, BS4 is not applied because segregation information is lacking.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: 'Missense variant in a gene where only loss of function causes disease'. The evidence shows: this is a loss-of-function frameshift variant, not missense. Therefore, BP1 is not applied because it does not apply to this variant type.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP2 is: 'Observed in trans with a pathogenic variant for dominant disorders or in cis with a pathogenic variant'. The evidence shows: no data on trans or cis observations with another variant. Therefore, BP2 is not applied because such observations are not documented.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: 'In-frame insertions/deletions in repetitive region without known function'. The evidence shows: this is a frameshift resulting in truncation, not an in-frame indel. Therefore, BP3 is not applied because it does not meet the criterion.
BP4
BP4 (Supporting)
According to standard ACMG guidelines, the rule for BP4 is: 'Multiple lines of computational evidence suggest no impact on gene or gene product'. The evidence shows: SpliceAI predicts minimal impact on splicing (score 0.01) and no deleterious computational predictions. Therefore, BP4 is applied at Supporting strength because computational evidence suggests no splicing impact.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP5 is: 'Variant found in a case with an alternate molecular basis for disease'. The evidence shows: no case reports describe an alternate molecular basis. Therefore, BP5 is not applied because no such cases exist.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: 'Reputable source reports variant as benign, but without accessible evidence'. The evidence shows: the variant is not reported in any reputable database as benign. Therefore, BP6 is not applied because no such reports are available.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP7 is: 'Synonymous variant with no predicted impact on splicing'. The evidence shows: this is a frameshift variant, not synonymous. Therefore, BP7 is not applied because it does not meet the criterion.