CREBBP c.6436C>T, p.(Gln2146Ter)

Reasoning

NM_004380.2:c.6436C>T is a transcript-relevant nonsense variant in the RefSeq-selected CREBBP transcript, producing NP_004371.2:p.(Gln2146Ter). Variant Validator places c.6436 in exon 31, the terminal coding exon, whose coding interval extends from c.5173 to c.*2664; therefore the premature termination codon is in the last exon and is predicted to escape the usual nonsense-mediated-decay mechanism. The normal protein is 2443 amino acids and the predicted product terminates at residue 2146, removing 297 amino acids (12.2%) from the C terminus. CREBBP loss of function is an established germline disease mechanism, and the generic ClinGen SVI PVS1 framework is applicable because no CREBBP CSPEC/VCEP specification was identified. Under the named ClinGen SVI PVS1 rule for a premature stop in the terminal exon, NMD escape requires downgrading from full PVS1 to strong; no evidence in the available case data establishes that this terminal region is a benign repeat-only or non-critical region warranting a further downgrade or non-application. Thus PVS1 is met at strong strength, not very strong strength, specifically because the stop codon lies in the terminal exon and is predicted to escape NMD.

Rule

ClinGen SVI PVS1 recommendations (PMC6185798): a premature termination codon in the terminal exon is predicted to escape NMD and is downgraded from full PVS1 to strong; further downgrade requires evidence of a non-critical affected region.

Evidence considered

• The normalized variant is NM_004380.2:c.6436C>T, a nonsense change yielding NP_004371.2:p.(Gln2146Ter).
• Variant Validator identifies NM_004380.2 as the RefSeq-selected CREBBP transcript and places the variant in exon 31, the terminal coding exon.
• The exon map gives the terminal exon coding interval as c.5173-c.*2664, encompassing c.6436.
• The reference protein length is 2443 amino acids and the predicted termination is at residue 2146, removing 297 amino acids, or 12.2% of the protein.
• The CREBBP gene-level PVS1 gate is eligible because germline loss of function is supported as a disease mechanism.
• The ClinGen SVI PVS1 framework specifies downgrading a premature stop predicted to escape NMD in the terminal exon; this is the named rule applied here.
• No evidence establishes that the removed C-terminal segment is a benign repeat-only or non-critical region, so no additional downgrade or non-application was assigned.

Still missing

• No CREBBP-specific VCEP/CSPEC PVS1 specification or explicit terminal-domain criticality annotation was available; generic ClinGen SVI guidance was used.
• NMD escape is predicted from terminal-exon location rather than demonstrated by an assay in this case.

Sources

Reasoning

PM2 at supporting strength is met. The variant is absent from gnomAD v2.1 and gnomAD v4.1, and the available non-cancer records report it as absent in gnomAD v2.1 non-cancer and gnomAD v3.1 non-cancer. No population allele count or frequency is available to suggest a threshold artifact. Under the supplied generic ClinGen SVI recommendation, PM2 supporting applies at allele frequency <=0.0001; no applicable CREBBP-specific VCEP specification was available.

Rule

Apply PM2 at supporting strength when the variant is absent or has allele frequency <=0.0001 in an appropriate population database; no applicable CREBBP-specific VCEP rule was available.

Evidence considered

• gnomAD v2.1 reports the variant as absent.
• gnomAD v4.1 reports the variant as absent.
• The available gnomAD v2.1 non-cancer and v3.1 non-cancer records also report the variant as absent.
• The supplied generic ClinGen SVI PM2 recommendation uses allele frequency <=0.0001 for supporting strength (PMID:25741868).

Sources

Reasoning

The exact variant is classified Pathogenic in ClinVar, but the record has criteria provided by a single submitter and no expert-panel submission. Under the governing instruction for this group, PP5 applies only to an exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic classification; ordinary laboratory submissions must never trigger PP5. Therefore PP5 is not met.

Rule

PP5 requires an exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic classification; a single-submitter, ordinary laboratory, aggregate, or non-expert assertion is not eligible.

Evidence considered

• ClinVar variation 694717 exactly matches NM_004380.2:c.6436C>T and is classified Pathogenic by one clinical laboratory with review status 'criteria provided, single submitter'.
• The ClinVar submission audit reports expert_panel_submissions = 0.

Sources

Reasoning

BA1 is not met. The variant is absent from the available gnomAD v2.1 and gnomAD v4.1 records, including the reported non-cancer subsets, so its observed population frequency is not at or above the generic stand-alone threshold of 0.05. The generic BA1 threshold is the ACMG/AMP 2015 threshold (PMID:25741868); no CREBBP-specific VCEP specification was available.

Rule

Apply BA1 only when the observed population allele frequency is >=0.05 under the generic ACMG/AMP default; no applicable CREBBP-specific VCEP rule was available.

Evidence considered

• gnomAD v2.1 reports the variant as absent.
• gnomAD v4.1 reports the variant as absent.
• The available gnomAD v2.1 non-cancer and v3.1 non-cancer records also report the variant as absent.
• The generic ACMG/AMP 2015 BA1 stand-alone threshold supplied for this assessment is allele frequency >=0.05 (PMID:25741868).

Sources

Reasoning

BS1 is not met. The variant is absent from gnomAD v2.1 and gnomAD v4.1, including the reported non-cancer subsets, and therefore has no observed allele frequency reaching the generic BS1 threshold of 0.01. No CREBBP-specific population-frequency threshold or VCEP specification was available.

Rule

Apply BS1 only when the observed population allele frequency is >=0.01 under the supplied generic default; no applicable CREBBP-specific VCEP rule was available.

Evidence considered

• gnomAD v2.1 reports the variant as absent.
• gnomAD v4.1 reports the variant as absent.
• The available gnomAD v2.1 non-cancer and v3.1 non-cancer records also report the variant as absent.
• The generic BS1 threshold supplied for this assessment is allele frequency >=0.01; no CREBBP-specific threshold was available.

Sources

Reasoning

BS2 is not met because no healthy individual carrying this variant, including a healthy homozygote or other genotype relevant to the disease model, is reported in the available population evidence. The variant is absent from gnomAD v2.1 and v4.1 and from the available non-cancer subsets; absence does not provide positive BS2 evidence.

Rule

Apply BS2 only when the variant is observed in healthy individuals in a genotype incompatible with the disease model; absence is not positive BS2 evidence.

Evidence considered

• gnomAD v2.1 reports the variant as absent, providing no observed healthy carrier or homozygote.
• gnomAD v4.1 reports the variant as absent, providing no observed healthy carrier or homozygote.
• The available gnomAD v2.1 non-cancer and v3.1 non-cancer records also report the variant as absent.
• Because BS2 requires observation of the variant in healthy individuals, population absence cannot establish BS2.

Sources

Reasoning

No exact-variant ClinVar expert-panel classification of Benign or Likely benign is present. The only exact-variant ClinVar assertion is Pathogenic from a single laboratory, with zero expert-panel submissions. Under the governing instruction for this group, ordinary laboratory submissions, aggregate labels, and non-expert assertions cannot trigger BP6. Therefore BP6 is not met.

Rule

BP6 requires an exact-variant ClinVar expert-panel Benign or Likely benign classification; a single-submitter, ordinary laboratory, aggregate, or non-expert assertion is not eligible.

Evidence considered

• ClinVar variation 694717 exactly matches NM_004380.2:c.6436C>T and has one single-submitter Pathogenic assertion.
• The ClinVar submission audit reports expert_panel_submissions = 0 and no Benign or Likely benign assertion.

Sources

Reasoning

PS2 requires documented de novo occurrence in the affected proband with confirmed maternity and paternity, ideally including appropriate parental testing and consideration of parental mosaicism. The available case evidence identifies the variant as NM_004380.2:c.6436C>T (p.Gln2146Ter) and records ClinVar origin as unknown, but provides no proband-level parental genotypes, maternity/paternity confirmation, or de novo testing result. Therefore PS2 cannot be assessed.

Rule

Generic ACMG/AMP PS2: de novo occurrence in a patient with the disease and no family history, with maternity and paternity confirmed; strength may depend on the quality and completeness of parental testing.

Evidence considered

• The variant is identified as NM_004380.2:c.6436C>T (NP_004371.2:p.(Q2146*)).
• The ClinVar submission records origin as unknown and does not provide de novo or parental-testing evidence.
• No proband-level parental genotypes, maternity/paternity confirmation, or de novo result is available in the reviewed case evidence.

Still missing

• Documented variant testing results for the proband and both biological parents
• Confirmation of maternity and paternity
• Assessment for parental mosaicism if the variant is reported as de novo

Reasoning

No validated functional study directly tested CREBBP NM_004380.2:c.6436C>T (p.Gln2146Ter). PMID:21390130 reports functional assays for selected CREBBP mutants in relapsed acute lymphoblastic leukemia models, including effects on histone H3 lysine 18 acetylation, target-gene expression, proliferation, and drug response, but the exact p.Gln2146Ter variant was not mentioned and those results cannot be transferred to this variant. The available case evidence therefore does not establish variant-specific abnormal function at any PS3 strength.

Evidence considered

• PMID:21390130 describes functional testing of selected CREBBP mutants but does not mention c.6436C>T or p.Gln2146Ter; its results cannot be assigned to this exact variant.
• No CREBBP-specific VCEP or gene-specific functional calibration was available, so generic ACMG/AMP functional evidence principles were used only to determine that variant-specific assay evidence is required.

Still missing

• A validated cellular, biochemical, or other disease-relevant assay directly testing p.Gln2146Ter is unavailable in the reviewed evidence.

Sources

Reasoning

No case-control study, statistically supported affected-versus-control enrichment, odds ratio, likelihood ratio, or qualifying aggregate case count for NM_004380.2:c.6436C>T was identified. PMID:21390130 concerns somatic CREBBP mutations in relapsed acute lymphoblastic leukaemia and explicitly does not mention this exact variant; the ClinVar record supplies no case-control data. Therefore PS4 cannot be assessed.

Rule

Generic ACMG/AMP PS4 requires significantly increased prevalence of the variant in affected individuals compared with appropriate controls; no variant-specific numeric enrichment threshold or qualifying dataset is available.

Evidence considered

• The exact ClinVar record for NM_004380.2:c.6436C>T contains one single-submitter clinical laboratory assertion and no case-control statistics.
• PMID:21390130 reports somatic CREBBP mutations in relapsed acute lymphoblastic leukaemia but does not mention c.6436C>T or p.(Q2146*).

Still missing

• A variant-specific case-control or statistically supported case-enrichment dataset is unavailable.

Sources

Reasoning

PM6 requires a credible report of de novo occurrence when maternity and/or paternity has not been confirmed. The available evidence does not report a de novo observation for this variant or provide a case-level inheritance description; the single ClinVar submission records origin as unknown. Consequently, PM6 cannot be assessed.

Rule

Generic ACMG/AMP PM6: assumed de novo occurrence in a patient with the disease, without confirmation of maternity and/or paternity.

Evidence considered

• The available ClinVar submission records the variant origin as unknown.
• The reviewed evidence contains no case-level de novo statement, parental testing result, or inheritance description for NM_004380.2:c.6436C>T.

Still missing

• A case-level report documenting de novo occurrence
• Available parental testing information, even if maternity or paternity is unconfirmed
• Phenotypic and clinical context for the alleged de novo proband

Reasoning

PP1 requires cosegregation of the variant with disease in multiple affected family members, with strength determined by the number of informative meioses and the reliability of phenotype assignment. The available case evidence contains no affected relatives, family pedigree, variant-positive relatives, variant-negative relatives, or informative meioses. The listed ClinVar condition labels describe phenotypic features but do not establish familial segregation. Therefore PP1 cannot be assessed.

Rule

Generic ACMG/AMP PP1: cosegregation with disease in multiple affected family members; evidence strength increases with the number of informative meioses and the quality of phenotype ascertainment.

Evidence considered

• The ClinVar submission lists low hanging columella, broad hallux, moderate intellectual disability, and microcephaly as condition labels, but provides no familial segregation data.
• No pedigree, affected-relative testing, unaffected-relative testing, or informative meiosis count is available in the reviewed case evidence.

Still missing

• Pedigree and number of informative meioses
• Phenotype status of relatives
• Variant genotypes for affected and unaffected relatives
• Segregation analysis accounting for phenotype specificity and possible reduced penetrance

Reasoning

The exact ClinVar submission lists low hanging columella, broad hallux, moderate intellectual disability, and microcephaly, but it is a single laboratory assertion without a clinical case report, diagnostic assessment, or documentation that the patient's phenotype is highly specific for Rubinstein-Taybi syndrome. The available literature extraction does not mention the exact variant. The phenotype-specificity evidence is therefore insufficient to apply PP4.

Rule

Generic ACMG/AMP PP4 may be applied when the patient's phenotype or family history is highly specific for a disease with a single-gene etiology; the available record does not establish that specificity.

Evidence considered

• The exact ClinVar submission lists low hanging columella, broad hallux, moderate intellectual disability, and microcephaly as condition labels.
• The submission is from one clinical laboratory and does not provide a case narrative or independent phenotype-specificity assessment.

Still missing

• A verified clinical case description and assessment of phenotype specificity for Rubinstein-Taybi syndrome are unavailable.

Sources

Reasoning

No validated functional study directly demonstrated preserved function for CREBBP NM_004380.2:c.6436C>T (p.Gln2146Ter). PMID:21390130 reports assays of selected CREBBP mutants, but the exact p.Gln2146Ter variant was not mentioned; absence of a variant-specific assay means that normal function cannot be established and BS3 cannot be applied at any strength.

Evidence considered

• PMID:21390130 does not mention c.6436C>T or p.Gln2146Ter and therefore provides no variant-specific evidence of preserved function.
• No validated benign functional result, appropriate controls, or disease-relevant assay demonstrating normal CREBBP function for this exact variant was identified.

Still missing

• A validated assay directly testing p.Gln2146Ter and demonstrating preserved function is unavailable in the reviewed evidence.

Sources

Reasoning

BS4 requires lack of segregation in affected family members or, in the relevant context, observation of the variant in unaffected family members when the disorder is expected to be penetrant and phenotype ascertainment is adequate. The available evidence contains no familial genotypes, unaffected-carrier observations, pedigree, or phenotype and age-of-onset information for relatives. A ClinVar origin of unknown is not evidence of non-segregation. Thus BS4 cannot be assessed.

Rule

Generic ACMG/AMP BS4: lack of segregation in affected members of a family; assessment requires reliable familial genotypes and adequately ascertained phenotypes, with consideration of penetrance and age of onset.

Evidence considered

• The available ClinVar submission records origin as unknown and does not report familial genotypes or non-segregation.
• No unaffected carriers, affected non-carriers, pedigree, or relative phenotype and age-of-onset data are available in the reviewed case evidence.

Still missing

• Genotypes and clinical status of relevant relatives
• Pedigree-based assessment of affected and unaffected family members
• Age, phenotype ascertainment, and penetrance context for unaffected relatives

Reasoning

BP2 cannot be assessed from the available evidence. Under the generic ACMG/AMP framework, BP2 requires the variant to be observed in trans with a pathogenic variant for a recessive disorder or in cis with a pathogenic variant for a dominant disorder. The case materials document no second variant, affected proband, parental testing, or cis/trans phase information for NM_004380.2:c.6436C>T.

Rule

Generic ACMG/AMP BP2: variant observed in trans with a pathogenic variant for a recessive disorder or in cis with a pathogenic variant for a dominant disorder.

Evidence considered

• The case materials provide no affected-proband observation, second allele, parental genotype, molecular phasing result, or cis/trans relationship for NM_004380.2:c.6436C>T.
• The generic ACMG/AMP BP2 definition requires either occurrence in trans with a pathogenic variant for a recessive disorder or occurrence in cis with a pathogenic variant for a dominant disorder; neither configuration is documented here.
• No gene-specific CREBBP VCEP specification was available, so no alternative BP2 rule or phase threshold supersedes the generic framework.

Still missing

• A documented second variant in the same individual and its pathogenicity status.
• Validated cis/trans phase information, including parental or molecular phasing data.
• Affected-proband context sufficient to determine whether BP2's dominant or recessive configuration applies.

Reasoning

No evidence was identified that the patient's phenotype or disease presentation is better explained by a pathogenic variant in another gene, and no alternate molecular diagnosis is documented. The available ClinVar record is not evidence of an alternate cause. Therefore BP5 cannot be assessed.

Rule

Generic ACMG/AMP BP5 requires a pathogenic variant in another gene that better explains the patient's phenotype; no such evidence is available.

Evidence considered

• The case evidence contains no documented alternate pathogenic variant or alternative molecular diagnosis.

Still missing

• An independently documented alternate molecular cause is unavailable.