PTCH1 c.2588G>A, p.(Trp863Ter)

Reasoning

NM_000264.4:c.2588G>A is a nonsense variant in PTCH1, producing NP_000255.2:p.(Trp863Ter) and truncating the 1,448-amino-acid protein at residue 863, with loss of 586 C-terminal amino acids. VariantValidator places it in exon 16, while the transcript has additional downstream coding exons; therefore the premature termination codon is well upstream of the final exon-exon junction and is expected to trigger nonsense-mediated decay rather than escape NMD. NM_000264.4 is the RefSeq-selected transcript for PTCH1, and PTCH1 loss of function is an established germline disease mechanism in the available gene-level literature. No applicable PTCH1 VCEP or CSPEC specification was identified, so the generic ClinGen SVI PVS1 framework applies. There is no evidence that this is a non-critical distal truncation, a repeat-region artifact, or a region enriched for benign loss-of-function variation. The full, un-downgraded PVS1 strength is therefore warranted: very strong.

Rule

Generic ClinGen SVI PVS1 framework (PMC6185798): qualifying premature-termination variant in a gene with an established loss-of-function disease mechanism; full strength retained because the variant is in an upstream coding exon and is expected to undergo NMD, without a specified downgrade condition.

Evidence considered

• The normalized consequence is NM_000264.4:c.2588G>A, NP_000255.2:p.(Trp863Ter), a nonsense change that truncates PTCH1 from 1,448 amino acids to 862 residues before the premature stop.
• VariantValidator assigns the variant to exon 16; the transcript annotation shows multiple downstream coding exons, supporting a premature termination codon sufficiently upstream of the terminal exon-exon junction for expected nonsense-mediated decay.
• NM_000264.4 is the RefSeq-selected PTCH1 transcript, and the transcript-level annotation is concordant with the normalized p.(Trp863Ter) consequence.
• PTCH1 loss of function is supported as a germline disease mechanism by the gene-context assessment and literature-level evidence describing inactivating, truncating PTCH mutations in nevoid basal cell carcinoma syndrome.
• The generic ClinGen SVI PVS1 framework is applicable because no PTCH1-specific VCEP or CSPEC specification was available; no named downgrade rule for NMD escape, a non-critical exon, or a distal non-critical region is triggered.

Sources

Reasoning

No applicable PTCH1-specific VCEP or gene framework was available, so generic ACMG/AMP population evidence rules were used. The variant is absent from the default all-comers gnomAD v2.1 and gnomAD v4.1 datasets, supporting PM2 for a rare disease-associated variant. The case bundle also records absence in the available non-cancer subsets, but no framework required substituting those subsets for the default sources.

Rule

Generic ACMG/AMP PM2: apply at supporting strength when the variant is absent, or extremely rare, in appropriate population databases and the disease context is compatible; no PTCH1-specific modification was available.

Evidence considered

• The default all-comers gnomAD v2.1 record reports the variant as absent.
• The default all-comers gnomAD v4.1 record reports the variant as absent.
• The generic ACMG/AMP framework publication (Richards et al., PMID:25741868) supports PM2 when a variant is absent or extremely rare in appropriate population databases; this variant is absent from both default datasets.
• The case bundle additionally records absence in gnomAD v2.1 non-cancer and gnomAD v3.1 non-cancer subsets; because no applicable VCEP specified a non-cancer or exome-only source, the default all-comers records were used for the formal assessment.

Sources

Reasoning

PP5 was evaluated under the required exact-variant ClinVar expert-panel rule. ClinVar variation 954253 exactly matches PTCH1 c.2588G>A (p.Trp863Ter) and is classified Pathogenic, but its review status is criteria provided, single submitter, with zero expert-panel submissions. This ordinary laboratory assertion cannot trigger PP5.

Rule

PP5 applies only to an exact-variant ClinVar expert-panel classification of Pathogenic or Likely pathogenic; ordinary single-submitter assertions are excluded.

Evidence considered

• ClinVar variation 954253 is an exact match for PTCH1 c.2588G>A (p.Trp863Ter), classified Pathogenic with review status criteria provided, single submitter; the submission audit reports expert_panel_submissions = 0.
• Under the governing rule, ordinary laboratory submissions, aggregate labels, and non-expert assertions do not trigger PP5.

Still missing

• No exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic classification is present.

Sources

Reasoning

No applicable PTCH1-specific VCEP or gene framework was available, so generic ACMG/AMP population evidence rules were used. The variant is absent from the default all-comers gnomAD v2.1 and gnomAD v4.1 datasets; therefore, the BA1 threshold of a sufficiently high population allele frequency (generally >5%) is not met.

Rule

Generic ACMG/AMP BA1: apply only when the population allele frequency is above the established stand-alone benign threshold, generally >5%; absence does not meet BA1.

Evidence considered

• The default all-comers gnomAD v2.1 record reports the variant as absent.
• The default all-comers gnomAD v4.1 record reports the variant as absent.
• The generic ACMG/AMP framework publication (Richards et al., PMID:25741868) uses a population-frequency threshold above 5% for BA1; the observed frequency here is zero because the variant is absent.
• The case bundle also records absence in the available gnomAD v2.1 non-cancer and v3.1 non-cancer subsets; no applicable VCEP required those subsets for this assessment.

Sources

Reasoning

No applicable PTCH1-specific VCEP or gene framework was available, so generic ACMG/AMP population evidence rules were used. The variant is absent from the default all-comers gnomAD v2.1 and gnomAD v4.1 datasets, with no observed allele frequency exceeding a disease-specific benign threshold; therefore BS1 is not met.

Rule

Generic ACMG/AMP BS1: apply when the allele frequency is greater than expected for the disorder; an absent variant cannot satisfy this benign-frequency criterion.

Evidence considered

• The default all-comers gnomAD v2.1 record reports the variant as absent.
• The default all-comers gnomAD v4.1 record reports the variant as absent.
• The generic ACMG/AMP framework publication (Richards et al., PMID:25741868) defines BS1 as a frequency greater than expected for the disorder; no observed frequency is available here because the variant is absent.
• No VCEP-specific disease-prevalence, penetrance, or maximum credible allele-frequency threshold was available for PTCH1 in this case.

Sources

Reasoning

BP6 was evaluated under the required exact-variant ClinVar expert-panel rule. ClinVar variation 954253 exactly matches PTCH1 c.2588G>A (p.Trp863Ter), is classified Pathogenic with review status criteria provided, single submitter, and has zero expert-panel submissions. No qualifying expert-panel Benign or Likely benign classification is present, so BP6 is not met.

Rule

BP6 applies only to an exact-variant ClinVar expert-panel classification of Benign or Likely benign; ordinary single-submitter assertions are excluded.

Evidence considered

• ClinVar variation 954253 is an exact match for PTCH1 c.2588G>A (p.Trp863Ter), classified Pathogenic with review status criteria provided, single submitter; the submission audit reports expert_panel_submissions = 0.
• Under the governing rule, ordinary laboratory submissions, aggregate labels, and non-expert assertions do not trigger BP6.

Still missing

• No exact-variant ClinVar expert-panel Benign or Likely benign classification is present.

Sources

Reasoning

PS2 requires a confirmed de novo occurrence in the proband, with verified maternity and paternity. The available evidence contains no proband-specific parental genotypes, maternity or paternity confirmation, or documented de novo observation for NM_000264.4:c.2588G>A (p.Trp863Ter). The reviewed PTCH1 literature provides gene-level or unrelated-variant context but does not document this exact variant as de novo.

Rule

Generic ACMG/AMP PS2: confirmed de novo variant in a patient with disease and no family history, with maternity and paternity confirmed; absent case-specific confirmation, do not apply.

Evidence considered

• The case materials identify NM_000264.4:c.2588G>A (NP_000255.2:p.(Trp863Ter)) in PTCH1 but provide no proband-specific parental testing or de novo documentation.
• The reviewed PTCH1 cohort paper studied 143 individuals from 106 pedigrees, but the extracted finding does not report this exact variant or a de novo result for it.

Still missing

• Proband identity and phenotype linked to the variant
• Maternal and paternal genotypes
• Maternity and paternity confirmation
• Direct documentation that the variant is absent from both parents

Sources

Reasoning

No validated functional study directly tested NM_000264.4:c.2588G>A (NP_000255.2:p.(Trp863Ter)). The available PTCH1 literature provides gene- or pathway-level context or assays of different truncating variants, without variant-specific results, appropriate wild-type and loss-of-function controls, replicate data, or a quantitative disease-relevant readout for p.(Trp863Ter). No PTCH1-specific VCEP/CSPEC specification was available, so the generic ACMG/AMP framework applies; a predicted nonsense consequence and functional results from other PTCH1 variants cannot substitute for direct functional evidence. PS3 is therefore not assessed.

Rule

Generic ACMG/AMP PS3: apply only when well-established functional studies show an effect on protein function or a validated disease-relevant assay; no strength is assigned without direct, adequately controlled variant-specific evidence.

Evidence considered

• PMID:24840883 tested different PTCH1 truncating variants, p.C727VfsX745 and p.S733IfsX736, using cell-based proliferation, GLI1-reporter, cell-cycle, binding, and localization assays; NM_000264.4:c.2588G>A (p.(Trp863Ter)) was not mentioned.
• PMID:41748949 tested different engineered PTCH1 C-terminal truncations in colorectal cancer cells and mice; the reported tumorigenic effects do not directly test p.(Trp863Ter).
• PMID:22670903 measured pathway-related GLI1 and PTCH2 expression in basal-cell carcinoma and described PTCH1 loss-of-function biology, but did not test the queried variant.
• PMID:24523439 describes the disease relevance of PTCH1 loss-of-function and Hedgehog-pathway activation but reports no functional assay for p.(Trp863Ter).
• PMID:8782823 did not provide usable scientific findings or variant-specific functional evidence in the supplied text.
• The variant is a predicted nonsense change, NM_000264.4:c.2588G>A, p.(Trp863Ter), but consequence prediction and assays of other PTCH1 variants do not meet the generic PS3 requirement for variant-specific functional evidence.
• No PTCH1-specific VCEP/CSPEC framework was available; the generic ACMG/AMP framework was therefore used.

Still missing

• A variant-specific assay measuring PTCH1 function or a validated disease-relevant readout is unavailable.
• No quantitative comparison with wild-type and known PTCH1 loss-of-function controls, assay replicates, or control performance data is available for this variant.

Sources

Reasoning

No PTCH1-specific VCEP framework was available, so generic ACMG/AMP PS4 was considered. The supplied evidence contains no exact-variant case-control study, affected-case and control counts, odds ratio, or other validated enrichment statistic. The reviewed PTCH1 literature describes gene-level mutation patterns and does not report this exact c.2588G>A (p.Trp863Ter) variant, so it cannot establish PS4.

Rule

Generic ACMG/AMP PS4: statistically increased prevalence of the variant in affected individuals compared with controls; no exact-variant enrichment statistic was available.

Evidence considered

• PMID:16301862 reports PTCH mutation testing in 143 individuals from 106 pedigrees and lists nonsense mutations, but does not report the exact p.Trp863Ter variant or a case-control enrichment analysis.
• PMID:16419085 analyzes 284 PTCH mutations and 48 SNPs and discusses germline truncating mutations, but does not provide an exact-variant prevalence or enrichment statistic.

Still missing

• Exact-variant affected-case and control counts or a validated enrichment statistic are missing.
• The reviewed papers do not report the exact p.Trp863Ter variant.

Sources

Reasoning

PM6 requires a presumed de novo occurrence when maternity and paternity are not confirmed. The available evidence contains no proband-specific family history, parental genotypes, evidence of parental absence, or clinical documentation supporting presumed de novo status for NM_000264.4:c.2588G>A (p.Trp863Ter). No reviewed paper documents this exact variant as presumed de novo.

Rule

Generic ACMG/AMP PM6: presumed de novo occurrence without confirmed maternity and paternity; absent case-specific evidence, do not apply.

Evidence considered

• The case materials provide no proband-specific family history, parental genotypes, or presumed de novo assessment for this PTCH1 variant.
• The reviewed PTCH1 publications do not report NM_000264.4:c.2588G>A (p.Trp863Ter) as a de novo or presumed de novo variant.

Still missing

• Proband-specific family history
• Parental genotype information or evidence of parental absence
• Clinical documentation supporting presumed de novo status

Sources

Reasoning

PP1 requires co-segregation of the variant with disease in affected family members, with strength determined by the number and informativeness of observed meioses. The available evidence contains no affected relatives, unaffected relatives, family genotypes, phenotype assessments, or meiosis count for NM_000264.4:c.2588G>A (p.Trp863Ter). The reviewed publications provide no exact-variant segregation data.

Rule

Generic ACMG/AMP PP1: co-segregation with disease in multiple affected family members; apply only when informative family genotypes and phenotypes are documented.

Evidence considered

• No family pedigree, relative genotypes, phenotype concordance, or informative meiosis count is present for this variant.
• The reviewed PTCH1 mutation literature does not report this exact variant or a usable segregation series for it.

Still missing

• Family pedigree and affected-relative phenotypes
• Genotypes of affected and unaffected relatives
• Number of informative meioses
• Independent confirmation of variant and phenotype status

Sources

Reasoning

No PTCH1-specific VCEP framework was available, so generic ACMG/AMP PP4 was considered. PP4 requires a highly specific patient phenotype or family history consistent with a disease associated with the gene. The supplied materials identify Gorlin syndrome as the ClinVar condition, but provide no patient-level phenotype, diagnostic findings, or family history for this case; gene-level disease descriptions cannot establish PP4.

Rule

Generic ACMG/AMP PP4: patient phenotype or family history is highly specific for a disease associated with the gene; patient-level phenotype evidence was unavailable.

Evidence considered

• The exact ClinVar record labels the condition as Gorlin syndrome, but it is a single-submitter laboratory assertion and provides no phenotype for the individual being assessed.
• PMID:16301862 and PMID:16419085 provide PTCH1/NBCCS disease context but no patient-level phenotype or exact-variant clinical presentation.

Still missing

• Patient-level phenotype and diagnostic findings are missing.
• Family history and phenotype specificity relative to PTCH1-associated Gorlin syndrome are missing.

Sources

Reasoning

No applicable PTCH1-specific VCEP or gene framework was available, so generic ACMG/AMP population evidence rules were used. The available gnomAD records report absence rather than the presence of the variant in healthy adults, and they provide no documented healthy homozygote or hemizygote observation for this variant; therefore the BS2 observation requirement cannot be assessed.

Rule

Generic ACMG/AMP BS2: apply when the variant is observed in healthy adults, including homozygotes or hemizygotes where relevant, for a disorder expected to be highly penetrant; absence alone is insufficient.

Evidence considered

• The available gnomAD v2.1 and v4.1 records report the variant as absent and do not document healthy carriers or homozygotes.
• Absence from a population database is not equivalent to evidence that the variant occurs in healthy adults and therefore does not establish BS2.

Still missing

• A population or clinical dataset documenting unaffected adult carriers, or homozygotes where relevant, is needed to evaluate BS2.
• No penetrance-specific PTCH1 framework was available to define the appropriate healthy-observation context.

Sources

Reasoning

No validated functional study directly tested NM_000264.4:c.2588G>A (NP_000255.2:p.(Trp863Ter)) and demonstrated preserved PTCH1 function. The available publications either describe general PTCH1 loss-of-function biology or test different truncating variants; none provides a variant-specific benign functional result with suitable wild-type and disease-relevant controls, quantitative measurements, and replication. No PTCH1-specific VCEP/CSPEC specification was available, so the generic ACMG/AMP framework applies. BS3 is therefore not assessed.

Rule

Generic ACMG/AMP BS3: apply only when well-established functional studies show no damaging effect on protein function or a validated disease-relevant assay; no strength is assigned without direct, adequately controlled variant-specific benign evidence.

Evidence considered

• PMID:24840883 reports functional effects for different PTCH1 truncating variants, p.C727VfsX745 and p.S733IfsX736, not a benign-function result for p.(Trp863Ter).
• PMID:41748949 reports tumor-promoting effects for different engineered PTCH1 C-terminal truncations and does not test p.(Trp863Ter).
• PMID:22670903 provides PTCH1 pathway context and tumor-expression measurements but no variant-specific functional result for the queried variant.
• PMID:24523439 provides general PTCH1 loss-of-function and Hedgehog-pathway context but no assay demonstrating preserved function for p.(Trp863Ter).
• PMID:8782823 did not provide usable scientific findings or variant-specific functional evidence in the supplied text.
• No PTCH1-specific VCEP/CSPEC framework was available; the generic ACMG/AMP framework was therefore used.

Still missing

• A variant-specific assay demonstrating retained PTCH1 function is unavailable.
• No quantitative benign-function result, wild-type comparison, disease-relevant control, assay replication, or control-performance data is available for this variant.

Sources

Reasoning

BS4 requires a lack of segregation in affected family members, with reliable phenotype assessment and informative genotyping. The available evidence contains no affected-family-member genotypes, phenotype assessments, or non-segregation observations for NM_000264.4:c.2588G>A (p.Trp863Ter). Therefore, absence of reported segregation cannot be treated as evidence of non-segregation.

Rule

Generic ACMG/AMP BS4: lack of segregation in affected members of a family; do not infer non-segregation from missing family data.

Evidence considered

• The case materials contain no documented affected relatives, relative genotypes, or phenotype-genotype discordance for this PTCH1 variant.
• No reviewed publication provides exact-variant non-segregation evidence.

Still missing

• Affected-relative phenotype assessments
• Genotypes for affected relatives
• Documented discordance between variant status and disease status
• Assessment of phenocopies and reduced penetrance

Sources

Reasoning

No PTCH1-specific VCEP or gene-specific framework was available, so generic ACMG/AMP criteria were used. BP2 requires a documented allelic configuration with another pathogenic variant, including trans phase for a fully penetrant dominant disorder or cis phase when the inheritance context supports a benign interpretation. The available evidence contains no second pathogenic or likely pathogenic variant in the same individual, no molecular or family-based phase result, and no affected-proband genotype or segregation information for NM_000264.4:c.2588G>A (p.Trp863Ter). BP2 therefore cannot be assessed and is not applied.

Rule

Generic ACMG/AMP BP2: apply when the variant is observed in trans with a pathogenic variant for a fully penetrant dominant disorder, or in cis with a pathogenic variant when the configuration supports benignity; phase must be documented.

Evidence considered

• The available case evidence does not document a second pathogenic or likely pathogenic variant in the same individual as NM_000264.4:c.2588G>A (p.Trp863Ter).
• No cis/trans phase determination, affected-proband genotype, or segregation result is provided, so the allelic requirement for BP2 cannot be evaluated.

Still missing

• No second pathogenic or likely pathogenic variant was documented in the same individual.
• No molecular or family-based phase result was identified.
• No affected-proband genotype or segregation information was identified.

Sources

Reasoning

No PTCH1-specific VCEP framework was available, so generic ACMG/AMP BP5 was considered. The supplied evidence does not document a molecularly established alternative genetic diagnosis explaining the patient's phenotype. No BP5-specific likelihood-ratio value or governing numeric threshold is present, and the single-submitter Pathogenic ClinVar assertion is not evidence of an alternative diagnosis; therefore BP5 cannot be assessed.

Rule

Generic ACMG/AMP BP5 concerns a pathogenic variant found in a patient with an alternative molecular diagnosis that explains the phenotype; required alternative-diagnosis evidence is absent.

Evidence considered

• The exact ClinVar record contains a single-submitter Pathogenic assertion for PTCH1 c.2588G>A and does not document an alternative molecular diagnosis.
• No BP5-specific VCEP rule, likelihood-ratio value, or threshold was available in the supplied framework materials.

Still missing

• A confirmed alternative genetic diagnosis explaining the phenotype is missing.
• No applicable BP5-specific numeric rule or threshold was supplied.

Sources