NM_001202543.1:c.2983C>T

CUX1 · NP_001189472.1:p.(Arg995Ter) · NM_001202543.1

GRCh37: chr7:101847713 C>T · GRCh38: chr7:102204433 C>T

Gene: CUX1 Transcript: NM_001202543.1

Final call

Pathogenic

PVS1 very strong PM2 supporting PP5 supporting

Variant details

Gene

CUX1

Transcript

NM_001202543.1

Protein

NP_001189472.1:p.(Arg995Ter)

gnomAD AF

0.0 (v2.1)

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Pathogenic classification based on the observed combination of very strong, strong, moderate, and supporting pathogenic criteria.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	Met	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.	pvs1_generic_framework PMID:37644171
PS1	N/A	PS1 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.
PS2	Not met	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.
PS3	Not assessed	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.
PS4	Not met	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.	PMID:37644171 gnomad_v2
PS5	N/A	PS5 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).
PM1	Not met	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.
PM2	Met	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).	gnomad_v2 gnomad_v4
PM5	N/A	PM5 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.
PM6	Not met	No publication reports this variant as assumed de novo (without confirmation of maternity/paternity). The exploratory search found no assumed de novo observations.
PP1	Not met	No cosegregation data are available. No family with multiple affected members carrying this variant has been reported.
PP2	Not met	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.
PP3	Not met	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.	spliceai bayesdel
PP4	Not met	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.
PP5	Met	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.	clinvar PMID:37644171
BA1	Not met	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.	gnomad_v2
BS1	Not met	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.	gnomad_v2
BS2	Not met	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.	gnomad_v2
BS3	Not assessed	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.
BS4	Not met	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.
BP1	Not met	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.
BP2	N/A	BP2 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.
BP3	N/A	BP3 applies to in-frame deletions or insertions in repetitive regions. This variant is a single nucleotide substitution, not an in-frame indel.
BP4	Not met	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.	spliceai bayesdel
BP5	Not met	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.
BP6	Not met	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.	clinvar
BP7	Not met	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.
PM3	N/A	PM3 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.
PM4	N/A	PM4 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.

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