CCND1 c.839_841del, p.(Glu280del)

Reasoning

BP3 (Richards et al. 2015, PMID:25741868) applies to in-frame insertions/deletions in a repeat region without known function. NM_053056.3:c.839_841del is an in-frame deletion of a single codon (p.Glu280del) in the last exon of the MANE Select transcript; protein length changes 295 -> 294 aa with no frameshift/stop, and SpliceAI predicts no splice impact (max delta 0.001), so the consequence is purely an in-frame protein change. The deleted codon is one unit of a low-complexity poly-glutamate trinucleotide repeat: ClinVar's HGVS title uses repeat-unit notation ('c.827AGG[4] (p.Glu280del)'), the residue sits within a ~10-residue poly-Glu run of NP_444284.1, and the gVCF representation (AGAG>A with a 13-nt shift) reflects a repeat-embedded deletion. No function specific to this poly-E repeat tract (or to its length) is documented in any source available in this case (literature_pass returned no PMIDs; fulltext_map empty), satisfying the 'without known function' leg at the level of available evidence. BP3 is therefore met at supporting (benign) strength. Human review is flagged because the poly-E tract lies within the C-terminal PEST-like region of cyclin D1, a region with general documented roles in protein stability/degradation, and no tract-specific functional data were retrievable to confirm or refute the 'without known function' leg.

Rule

BP3 (Richards et al. 2015, PMID:25741868): in-frame insertions/deletions in a repeat region without known function. Met at supporting (benign) strength for an in-frame single-codon deletion within a low-complexity poly-glutamate trinucleotide repeat.

Evidence considered

• Framework: no ClinGen CSPEC/VCEP exists for CCND1 (cspec not found; gene_vcep_dir null; vcep_materials framework_mode = generic_acmg_fallback); generic ACMG/AMP 2015 rules (Richards et al. 2015, PMID:25741868) govern PM4/BP3, as referenced by generic_acmg_combination_rules.
• In-frame status: prefetch normalization (Mutalyzer) predicts NP_444284.1:p.(Glu280del) from NM_053056.3:c.839_841del; a 3-nt deletion of one codon, so the reading frame is preserved, no premature stop, protein length 295 -> 294 aa.
• Repeat-region status - ClinVar variant title (source clinvar; only the sequence notation was used, not the record's classification): 'NM_053056.3(CCND1):c.827AGG[4] (p.Glu280del)' uses HGVS trinucleotide-repeat copy-number notation, i.e., NCBI represents this allele as a repeat contraction.
• Repeat-region status - protein context (prefetch normalization): Glu280 is the C-terminal-most residue of a homopolymeric poly-Glu run in NP_444284.1 (…KAAEEEEEEEEEVDL…), so the deletion removes one unit from a low-complexity amino acid repeat tract.
• Repeat-region status - gnomAD v2 variant id (source gnomad_v2): '11-69465987-AGAG-A' (ref AGAG > alt A) with a 13-nt shift in the normalized description indicates the deletion is embedded in a repeated motif.
• No splice impact (source spliceai): max delta score 0.001, so the in-frame protein change is the only predicted consequence; exon 5 is the terminal exon of NM_053056.3, so NMD is not a consideration.
• Function of the repeat tract: literature_pass.json contains no PMIDs and fulltext_map.json is empty; none of the retrieved sources (OncoKB gene-level note, COSMIC somatic count, pvs1_gene_context papers) documents a function of the CCND1 poly-E tract or of Glu280 specifically, so no known function for this repeat region is established in the available evidence.

Still missing

• No literature or functional data were available to establish whether the poly-E repeat tract (or its copy number) has a specific function in cyclin D1; the 'without known function' leg of BP3 rests on absence of documentation in this case's sources.
• The C-terminal region of cyclin D1 contains a PEST-like degradation signal; a reviewer may dispute 'without known function' for this tract, so human review of the BP3 assignment is recommended.

Sources

Reasoning

Same generic non-VCEP SpliceAI-only path applies (no CSPEC/VCEP for CCND1; variant is an in-frame deletion, not a missense substitution). SpliceAI max delta score = 0.001, below the 0.1 threshold for BP4, so BP4 is met at supporting strength.

Rule

generic_acmg_pp3_bp4_spliceai_nonmissense

Evidence considered

• SpliceAI Lookup predicts no significant splice impact for NM_053056.3:c.839_841del, max delta score = 0.001, below the 0.1 BP4 threshold in this lab's generic non-VCEP PP3/BP4 calibration.
• No CCND1 CSPEC/VCEP PP3/BP4 lookup material was found (cspec.found=false; vcep_materials note='no cspec url available'), so the generic ACMG fallback rule governs this criterion.

Sources

Reasoning

PM2 is not met because the variant is present in population databases: gnomAD v4.1 reports 295 alleles and one homozygote, and gnomAD v2.1 reports 162 alleles. Although it is absent from gnomAD-Canada v1.0, absence in that dataset does not override its established presence in gnomAD v2.1 and v4.1.

Rule

Generic ACMG/AMP PM2 requires absence or sufficiently rare occurrence in population databases; confirmed presence in gnomAD v2.1 and v4.1 prevents PM2.

Evidence considered

• gnomAD v4.1: 295/1,600,148 alleles, AF 0.000184358, with one homozygote.
• gnomAD v2.1: 162/254,610 alleles, AF 0.000636267, with zero homozygotes.
• gnomAD-Canada v1.0 reports the variant as absent, but this is a single population resource and does not make the variant absent from population databases overall.

Sources

Reasoning

PM4 (Richards et al. 2015, PMID:25741868) requires an in-frame insertion/deletion causing a protein length change in a NON-repeat region, or a stop-loss variant. NM_053056.3:c.839_841del is a 3-nt in-frame deletion predicting NP_444284.1:p.(Glu280del): protein length changes from 295 to 294 amino acids, no frameshift or stop codon, in exon 5 (the last exon) of the MANE Select transcript. However, the deleted codon is a one-unit contraction of a low-complexity poly-glutamate trinucleotide repeat: ClinVar's variant title uses HGVS repeat-unit notation ('NM_053056.3(CCND1):c.827AGG[4] (p.Glu280del)'), the deleted residue Glu280 is inside a run of ~10 consecutive glutamic acid residues in NP_444284.1 (…KAAEEEEEEEEEVDL…), and the gVCF/gnomAD representation (ref 'AGAG' > alt 'A', normalized with a 13-nt shift) is the characteristic signature of a deletion embedded in a repeat. Because the in-frame deletion lies in a repeat region, PM4's non-repeat-region prerequisite is not satisfied; in-frame indels in repeat regions are governed by BP3 instead. PM4 is therefore not met.

Rule

PM4 (Richards et al. 2015, PMID:25741868): protein length changes as a result of in-frame insertions/deletions in a NON-repeat region or stop-loss variants. Not met because the in-frame deletion lies within a repeat region.

Evidence considered

• Framework: no ClinGen CSPEC/VCEP exists for CCND1 (cspec not found; gene_vcep_dir null; vcep_materials framework_mode = generic_acmg_fallback); generic ACMG/AMP 2015 rules (Richards et al. 2015, PMID:25741868) govern PM4/BP3, as referenced by generic_acmg_combination_rules.
• Variant consequence (prefetch normalization, Mutalyzer): NM_053056.3:c.839_841del is a 3-nt in-frame deletion predicting NP_444284.1:p.(Glu280del); protein length 295 -> 294 aa; no frameshift and no stop codon introduced.
• Transcript relevance: NM_053056.3 is MANE Select for CCND1 (variant_validator mane_select=true); the variant is in exon 5, the last exon (c.724-*3192), so no nonsense-mediated decay would apply even to a truncating change; consequence is purely a protein-level in-frame single-residue deletion.
• SpliceAI (source spliceai): max delta score = 0.001 (DS_AG 0.0, DS_AL 0.001, DS_DG 0.001, DS_DL 0.0), i.e., no predicted splice impact; the variant acts as a coding-only consequence.
• Repeat-region evidence from ClinVar record (source clinvar, variant title only; the record's Likely benign classification was NOT used as evidence): 'NM_053056.3(CCND1):c.827AGG[4] (p.Glu280del)' — NCBI represents the allele with HGVS trinucleotide-repeat copy-number notation, indicating the deleted unit sits in a tandem repeat.
• Repeat-region evidence from protein context (prefetch normalization): the deleted Glu280 is within a low-complexity poly-glutamate tract in NP_444284.1 (C-terminal …KAAEEEEEEEEEVDLACTPTDVRDVDI*); Glu279 is also glutamate, so the deletion shortens a homopolymeric Glu run by one unit.
• Repeat-region evidence from gnomAD v2 variant id (source gnomad_v2): the variant is represented as '11-69465987-AGAG-A' (ref AGAG > alt A, i.e., a GAG unit removed) with the normalized description shifted 13 nt, the standard signature of a deletion embedded in a repeated motif.

Still missing

• The PM4 determination is contingent on designating the deleted codon as lying within a repeat region (poly-Glu tract). If a reviewer were to judge the poly-E tract as non-repetitive, PM4 would become the applicable in-frame-indel criterion and would be met at moderate strength; the repeat-region evidence (ClinVar repeat-unit HGVS notation, poly-E homopolymer context, repeat-embedded gVCF representation) is consistent across three independent sources.

Sources

Reasoning

No CSPEC/VCEP for CCND1 (cspec.found=false; vcep_materials note='no cspec url available'), so the generic ACMG in-silico framework applies. NM_053056.3:c.839_841del is an in-frame deletion (p.(Glu280del)), not a missense substitution, so per this lab's generic PP3/BP4 rule the SpliceAI-only path governs (REVEL/BayesDel were both explicitly skipped upstream as 'not snv or no coords', consistent with this being a non-SNV indel). SpliceAI max delta score = 0.001 (DS_AG 0.00, DS_AL 0.001, DS_DG 0.001, DS_DL 0.00), well below the 0.2 threshold required for PP3, so PP3 is not met.

Rule

generic_acmg_pp3_bp4_spliceai_nonmissense

Evidence considered

• SpliceAI Lookup (queried at https://spliceailookup.broadinstitute.org/#variant=NM_053056.3%3Ac.839_841del&hg=37&bc=basic&distance=500&mask=0&ra=0) predicts no significant splice impact for NM_053056.3:c.839_841del, max delta score = 0.001 (DS_AG=0.00, DS_AL=0.001, DS_DG=0.001, DS_DL=0.00).
• Generic ACMG PP3/BP4 in-silico calibration rule (this lab's non-VCEP fallback, applied because CCND1 has no CSPEC/VCEP-specific PP3/BP4 spreadsheet): for non-missense variants (including in-frame deletions), use SpliceAI only; max delta > 0.2 triggers PP3.
• REVEL and BayesDel scoring were both skipped upstream ('not snv or no coords') because this is an in-frame deletion, not an SNV; per the generic framework the missense/REVEL path is not applicable to this variant type.

Sources

Reasoning

PP5 is not met. ClinVar lists this exact variant as Likely benign from one clinical laboratory with no assertion criteria and zero review stars; it is not an expert-panel Pathogenic or Likely pathogenic classification.

Rule

PP5 may be applied only for an exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic classification; ordinary laboratory submissions and non-expert assertions are excluded.

Evidence considered

• ClinVar variation 3038710 for NM_053056.3:c.839_841del (p.Glu280del) is classified Likely benign by one clinical laboratory, with review status 'no assertion criteria provided' and 0 review stars.
• Under the requested rule, ordinary laboratory submissions, aggregate ClinVar labels, and non-expert assertions cannot trigger PP5; no exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic classification is present.

Sources

Reasoning

The variant is far below the generic ACMG/AMP stand-alone benign frequency range of 5%: gnomAD v4.1 reports AF 0.000184358 overall and maximum population AF 0.00152613 in East Asians; gnomAD v2.1 reports AF 0.000636267 overall and maximum population AF 0.00121547 in Ashkenazi Jewish individuals. Therefore BA1 is not met.

Rule

Generic ACMG/AMP BA1 stand-alone benign threshold: allele frequency greater than 5%; no applicable CCND1-specific framework was retrieved.

Evidence considered

• gnomAD v4.1: 295/1,600,148 alleles, total AF 0.000184358; highest reported population AF 0.00152613 in East Asians (67/43,902 alleles).
• gnomAD v2.1: 162/254,610 alleles, total AF 0.000636267; highest reported population AF 0.00121547 in Ashkenazi Jewish individuals (11/9,050 alleles).
• The observed frequencies are orders of magnitude below the generic BA1 stand-alone benign threshold of 5%; no gene-specific VCEP specification was available.

Sources

Reasoning

BP6 is not met. ClinVar lists this exact variant as Likely benign from one clinical laboratory with no assertion criteria and zero review stars; it is not an expert-panel Benign or Likely benign classification.

Rule

BP6 may be applied only for an exact-variant ClinVar expert-panel Benign or Likely benign classification; ordinary laboratory submissions and non-expert assertions are excluded.

Evidence considered

• ClinVar variation 3038710 for NM_053056.3:c.839_841del (p.Glu280del) is classified Likely benign by one clinical laboratory, with review status 'no assertion criteria provided' and 0 review stars.
• Under the requested rule, ordinary laboratory submissions, aggregate ClinVar labels, and non-expert assertions cannot trigger BP6; no exact-variant ClinVar expert-panel Benign or Likely benign classification is present.

Sources

Reasoning

No proband-level de novo observation or parental testing result is documented in the consolidated case-evidence bundle. Therefore, confirmed de novo occurrence cannot be established.

Rule

Generic ACMG/AMP PS2: de novo occurrence in a patient with the disease and no family history, with parental maternity/paternity and phenotype considerations addressed; stronger application requires confirmed parental testing.

Evidence considered

• The case-evidence bundle contains no proband description, pedigree, parental genotype results, trio testing report, or de novo statement for NM_053056.3:c.839_841del.
• The bundle reports no literature PMIDs and no relevant full-text publications for segregation or de novo assessment.

Still missing

• Proband genotype documentation for NM_053056.3:c.839_841del
• Validated testing results showing absence of the variant in both biological parents
• Assessment of parental relationships and relevant phenotype consistency

Reasoning

No CCND1-specific VCEP/CSpec functional assay specification exists for this gene (cspec.found=false, gene_vcep_dir=null), and no published functional/validated assay data (e.g., in vitro degradation, proliferation, transformation, or cell-cycle assays) for NM_053056.3:c.839_841del (p.Glu280del) were identified in the case bundle. OncoKB returned only gene-level context with no variant-specific reviewed functional evidence, and literature_pass/fulltext_map contain no PMIDs discussing this variant's functional characterization. Generic ACMG PS3 cannot be applied without validated assay evidence demonstrating a damaging effect with proper controls.

Evidence considered

• OncoKB (evidence.json) explicitly states no variant-specific reviewed functional evidence was found for CCND1 E280del; only gene-level amplification context in cancer is provided, which is not applicable to PS3 assay evidence.
• vcep_materials.json confirms no cspec/VCEP functional assay specification exists for CCND1 (cspec.found=false, gene_vcep_dir=null); framework_mode is generic_acmg fallback.
• literature_pass.json reports zero PMIDs found across evidence sources for this variant; fulltext_map.json is empty, so no full-text functional papers were available to review for PS3.

Still missing

• No validated functional assay (e.g., cyclin D1 degradation, proliferation, transformation) has been performed or reported for this specific in-frame deletion
• No CCND1 VCEP functional specification available to define assay validation thresholds

Reasoning

No case-control enrichment data, affected-case count, or statistically evaluated excess of this exact variant was available in the case-evidence bundle. PS4 therefore cannot be assessed.

Rule

Generic ACMG/AMP PS4 requires the variant to be significantly more prevalent in affected individuals than in controls; no applicable CCND1-specific specification was available.

Evidence considered

• The consolidated case-evidence bundle reports no literature PMIDs, no case series, and no case-control analysis for NM_053056.3:c.839_841del (NP_444284.1:p.Glu280del).

Still missing

• A case-control study or curated affected-case series for NM_053056.3:c.839_841del with an appropriate comparison group and statistical enrichment analysis is unavailable.

Reasoning

No applicable CCND1-specific VCEP framework was retrieved, so the generic ACMG/AMP framework applies. The case bundle contains no affected-proband observations, second pathogenic or likely pathogenic allele, phase information, or inheritance data establishing this variant in trans with a disease-causing variant for a recessive condition. PM3 therefore cannot be assessed from the available evidence.

Rule

Generic ACMG/AMP PM3 requires observation of the variant in trans with a pathogenic or likely pathogenic variant in an affected individual with a recessive condition; phase and disease-model support are required.

Evidence considered

• The consolidated case-evidence bundle reports no CSPEC/VCEP or gene-specific framework for CCND1 and falls back to generic ACMG/AMP.
• The consolidated case-evidence bundle contains no case-level family, affected-proband, allelic, phase, or inheritance observations relevant to PM3.
• No publication was identified or reviewed for PM3 in this case.

Still missing

• Affected-proband genotype and phenotype data are unavailable.
• No pathogenic or likely pathogenic variant in the same gene is documented for trans-phase evaluation.
• No parental testing, segregation, or other phase information is available.
• The inheritance model relevant to this CCND1-related condition is not established in the case bundle.

Reasoning

No credible de novo observation without parental confirmation is documented for this variant. The available records do not provide a proband, parental testing, or case-report description from which PM6 could be assessed.

Rule

Generic ACMG/AMP PM6: assumed de novo occurrence in a patient with the disease, when parental testing is unavailable or incomplete; it is distinct from confirmed de novo PS2.

Evidence considered

• The consolidated case-evidence bundle provides no case-level de novo report, parental testing information, or phenotype description for NM_053056.3:c.839_841del.
• No relevant publication was identified in the literature-pass or full-text map.

Still missing

• A documented affected proband carrying NM_053056.3:c.839_841del
• Evidence that the variant was considered de novo but parental testing was unavailable or incomplete
• Clinical phenotype and family-history details supporting the de novo interpretation

Reasoning

No affected or unaffected relatives, pedigree structure, informative meioses, or variant/phenotype co-segregation data are available. Segregation evidence therefore cannot be evaluated.

Rule

Generic ACMG/AMP PP1: cosegregation with disease in multiple affected family members in a gene known to cause the disease; strength depends on the number and informativeness of meioses and must not be applied without documented segregation data.

Evidence considered

• The consolidated case-evidence bundle contains no pedigree, family genotypes, affected-relative reports, unaffected-relative reports, or meiosis count.
• No applicable CCND1 VCEP or gene-specific framework was retrieved; the case uses generic ACMG/AMP fallback.

Still missing

• Pedigree identifying informative relatives and their disease status
• Genotypes for relatives tested for NM_053056.3:c.839_841del
• Phenotype assessment and number of informative meioses
• Any gene- or disease-specific segregation threshold

Reasoning

The bundle contains no patient phenotype description or phenotype-specific diagnostic assessment for the individual carrying this exact variant. PP4 cannot be assessed.

Rule

Generic ACMG/AMP PP4 requires the patient's phenotype or family history to be highly specific for a disease with a single-gene etiology; no applicable CCND1-specific specification was available.

Evidence considered

• The consolidated case-evidence bundle contains variant normalization and population/database findings but no individual-level phenotype, clinical features, or phenotype specificity assessment.

Still missing

• A sufficiently specific clinical phenotype for the tested individual and a documented match to a CCND1-related disorder are unavailable.

Reasoning

Population data show a maximum observed frequency of 0.00152613 in gnomAD v4.1 East Asians and 0.00121547 in gnomAD v2.1 Ashkenazi Jewish individuals, but the case bundle provides no CCND1 disease prevalence, penetrance estimate, allelic heterogeneity, or gene/disease-specific maximum credible allele frequency with which to compare these values. The frequency cannot therefore be adjudicated as above the expected disease frequency under a defensible BS1 threshold.

Rule

Generic ACMG/AMP BS1 requires an allele frequency greater than expected for the disorder; application requires a defensible disease-specific expected-frequency threshold.

Evidence considered

• gnomAD v4.1 reports total AF 0.000184358 and maximum population AF 0.00152613 in East Asians; one homozygote is reported in the dataset.
• gnomAD v2.1 reports total AF 0.000636267 and maximum population AF 0.00121547 in Ashkenazi Jewish individuals; no homozygotes are reported.
• The bundle contains no disease prevalence, penetrance, or validated CCND1-specific maximum credible allele-frequency calculation.

Still missing

• A defined CCND1-related disease prevalence and penetrance estimate is unavailable.
• A disease-specific maximum credible allele frequency or validated BS1 threshold is unavailable.
• The available ClinVar submission is an unreviewed single likely-benign assertion and cannot establish the BS1 population-frequency threshold.

Sources

Reasoning

gnomAD v4.1 reports one homozygote, but the bundle provides no individual-level age, phenotype, ascertainment, or health-status information for that homozygote. A database homozygote count alone does not demonstrate that the variant occurs in an unaffected adult or otherwise satisfy BS2, particularly without a defined CCND1 disease model and penetrance estimate.

Rule

Generic ACMG/AMP BS2 requires observation of the variant in healthy adults in a disorder expected to manifest early, or in healthy adults homozygous for a dominant disorder; individual-level unaffected status and disease-model context are required.

Evidence considered

• gnomAD v4.1 reports one homozygote among 1,600,148 alleles overall; the East Asian population also reports one homozygote.
• The dataset summary does not provide the homozygote's age, phenotype, clinical ascertainment, or confirmation as an unaffected adult.
• Because the necessary unaffected-person and disease-model information is absent, the homozygote observation is insufficient to meet BS2.

Still missing

• No individual-level clinical or age information is available for the reported gnomAD v4.1 homozygote.
• The CCND1-related disease inheritance model and penetrance are not established in the case bundle.
• No independent unaffected-adult homozygote observations are available.

Sources

Reasoning

No CCND1-specific VCEP/CSpec functional assay specification exists for this gene, and no published functional assay data with normal/wild-type-like results were identified for NM_053056.3:c.839_841del (p.Glu280del) in the case bundle. OncoKB provides only gene-level curated context, not variant-specific functional data. Without validated assay results (with appropriate controls) showing no damaging effect, BS3 cannot be applied.

Evidence considered

• OncoKB (evidence.json) explicitly states no variant-specific reviewed functional evidence was found for CCND1 E280del.
• vcep_materials.json confirms no cspec/VCEP functional assay specification exists for CCND1; framework_mode is generic_acmg fallback.
• literature_pass.json reports zero PMIDs found across evidence sources for this variant; fulltext_map.json is empty.

Still missing

• No validated functional assay data (of any result direction) exists for this variant to assess against BS3
• No CCND1 VCEP functional specification available to define assay validation thresholds

Reasoning

No unaffected relatives with reliable phenotype assessment and genotype results are documented. Absence of segregation cannot be established from the available evidence.

Rule

Generic ACMG/AMP BS4: lack of segregation in affected family members, based on appropriately evaluated relatives and a phenotype with sufficient penetrance; absence of family data is not evidence for BS4.

Evidence considered

• The consolidated case-evidence bundle contains no family pedigree, unaffected-relative phenotype information, or negative segregation testing for NM_053056.3:c.839_841del.
• The available population, ClinVar, somatic cancer, and splice-prediction records do not constitute BS4 evidence.

Still missing

• Unaffected relatives who were clinically assessed
• Validated genotypes for those relatives
• Pedigree and penetrance context sufficient to interpret non-segregation

Reasoning

No applicable CCND1-specific VCEP framework was retrieved, so the generic ACMG/AMP framework applies. The case bundle contains no affected or unaffected proband observations, no second variant for cis/trans determination, and no segregation or phase data showing this variant in trans with a pathogenic or likely pathogenic variant or in cis with a pathogenic variant. BP2 therefore cannot be assessed from the available evidence.

Rule

Generic ACMG/AMP BP2 requires observation of the variant in trans with a pathogenic or likely pathogenic variant for a dominant disorder, or in cis with a pathogenic variant; the relevant disease model and phase must be established.

Evidence considered

• The consolidated case-evidence bundle reports no CSPEC/VCEP or gene-specific framework for CCND1 and falls back to generic ACMG/AMP.
• The consolidated case-evidence bundle contains no case-level family, affected-proband, allelic, phase, or inheritance observations relevant to BP2.
• No publication was identified or reviewed for BP2 in this case.

Still missing

• No case-level allelic observations are available.
• No pathogenic or likely pathogenic comparator variant is documented.
• No cis/trans phase information is available.
• No inheritance or segregation data are available.

Reasoning

No individual-level clinical presentation or confirmed alternative molecular diagnosis is available to establish that another finding explains the patient's phenotype. BP5 cannot be assessed.

Rule

Generic ACMG/AMP BP5 requires a pathogenic variant in an alternative gene that explains the phenotype; no applicable CCND1-specific specification was available.

Evidence considered

• The consolidated case-evidence bundle provides no patient phenotype and no confirmed alternative pathogenic molecular finding that could explain a CCND1-related presentation.

Still missing

• A documented alternative molecular diagnosis that explains the tested individual's phenotype is unavailable.
• Individual-level phenotype information is unavailable.