CUX1 c.3580G>A, p.Val1194Ile
NM_001202543.1:c.3580G>A
COSMIC ID: COSM7408894
Variant of Uncertain Significance (VUS)
This missense variant (V1194I) in CUX1 is extremely rare and computational evidence supports a benign effect (BP4), but there are no functional, segregation, or case-control data to support pathogenicity or benignity beyond PM2 (Moderate) and BP4 (Supporting). Insufficient evidence leads to classification as Variant of Uncertain Significance.
ACMG/AMP Criteria Applied
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.3580G>A
Protein Change
V1194I
Location
Exon 22
(Exon 22 of 24)
5'Exon Structure (24 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 1194 in gene CUX1
Alternate Identifiers
COSM7408894
Variant interpretation based on transcript NM_001202543.1
Genome Browser
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HGVS InputNM_001202543:c.3580G>A
Active Tracks
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Clinical Data
Global Frequency
0.00084%
Very Rare
Highest in Population
European (non-Finnish)
0.00183%
Rare
Global: 0.00084%
European (non-Finnish): 0.00183%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 237960Alt: 2Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.00084%, 2/237960 alleles, homozygotes = 0) and at a higher frequency in the European (non-Finnish) population (MAF= 0.00183%, 2/109576 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
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 1194 in gene CUX1
Computational Analysis
Pathogenicity Predictions
REVEL Score
0.336
0.336
Likely Benign0.0
Uncertain (Low)0.2
Uncertain (Med)0.5
Likely Pathogenic0.75
REVEL scores ≥ 0.75 are strong evidence (PP3)
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Pathogenic:
polyphen_prediction: probably_damaging
Benign:
CADD: 5.66metasvm: Tmetalr: Tprimateai: T
Neutral: Show all
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1
PVS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, PVS1 is null variant in a gene where loss of function is a known mechanism of disease. The evidence for this variant shows it is a missense change (V1194I), not a null variant. Therefore, this criterion is not applied.
PS1
PS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, PS1 is the same amino acid change as a known pathogenic variant regardless of nucleotide change. The evidence for this variant shows no previously established pathogenic variant at residue V1194. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, PS2 is de novo (both maternity and paternity confirmed) in a patient with the disease. There is no de novo data for this variant. Therefore, this criterion is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, PS3 requires well-established functional studies supportive of a damaging effect. No functional characterization exists for V1194I. Therefore, this criterion is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PS4 is prevalence in affected individuals significantly increased compared with controls. No case-control data are available. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM1 is located in a mutational hotspot or well-established functional domain without benign variation. Domain or hotspot data for residue V1194 are unavailable. Therefore, this criterion is not applied.
PM2
PM2 (Moderate)
According to standard ACMG guidelines, PM2 is absent from controls (or at extremely low frequency if recessive). The evidence for this variant shows a MAF of 0.00084% in gnomAD, supporting rarity. Therefore, this criterion is applied at Moderate strength because the variant is extremely rare in population databases.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM3 is detected in trans with a pathogenic variant for recessive disorders. No trans or zygosity data are available. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM4 is protein length changes due to in-frame deletions/insertions. This is a missense variant without length change. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM5 is a novel missense change at an amino acid residue where a different pathogenic missense change has been seen. No pathogenic missense variants at V1194 are reported. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM6 is assumed de novo without confirmation. There is no de novo information. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP1 is co-segregation with disease in multiple affected family members. No family segregation data are available. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP2 is a missense variant in a gene with low rate of benign variation where missense is a common mechanism. Gene-specific constraint and missense mechanism data are lacking. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP3 is multiple lines of computational evidence support deleterious effect. Computational tools predominantly predict benign impact, not deleterious. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP4 is patient's phenotype highly specific for the gene. No phenotype data are provided. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP5 is a reputable source reporting variant as pathogenic without accessible evidence. No such reports exist. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to standard ACMG guidelines, BA1 is allele frequency >5% in controls. The allele frequency is far below that threshold. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, BS1 is allele frequency greater than expected for the disorder. The variant frequency is below thresholds for BS1. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, BS2 is observed in a healthy adult for a dominant disorder. No data on healthy adult carriers. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, BS3 is well-established functional studies show no damaging effect. No functional studies exist. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, BS4 is lack of segregation in affected family members. No segregation data are available. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP1 is missense variant in a gene where only loss of function causes disease. Mechanism of disease for CUX1 is not clearly established as only LoF. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP2 is observed in trans with a pathogenic variant for dominant disorders or in cis with a pathogenic variant. No phasing data. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP3 is in-frame indels in a repetitive region without known function. This is a missense variant. Therefore, this criterion is not applied.
BP4
BP4 (Supporting)
According to standard ACMG guidelines, BP4 is multiple lines of computational evidence suggest no impact. The evidence for this variant shows benign predictions from CADD, MetaSVM, MetaLR, PrimateAI, low REVEL score, and SpliceAI predicts no splicing impact. Therefore, this criterion is applied at Supporting strength because computational data indicate benign effect.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP5 is variant found in a case with an alternate molecular basis for disease. No case reports with alternate molecular diagnoses. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP6 is a reputable source reports variant as benign without accessible evidence. No such reports exist. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP7 is synonymous variant with no predicted splicing impact. This is a missense variant. Therefore, this criterion is not applied.