SETBP1 c.575A>G, p.(His192Arg)

Reasoning

Two independent calibrated in-silico lines converge on a benign-supporting call. Missense path: REVEL score of 0.101 is well below the ClinGen SVI-calibrated benign-supporting threshold (REVEL<=0.290) established by Pejaver et al. (PMID 36413997), supporting BP4. Splice-impact path: SpliceAI predicts no meaningful splicing effect (max delta score = 0.028, all four delta scores <0.03), well below the standard 0.2 actionable-splice threshold, further supporting that this substitution behaves as a simple missense change with no predicted splice consequence, consistent with BP4. Both lines are convergent evidence for the single BP4 code (applied once, supporting strength per ACMG/AMP 2015 default) and are not double-counted as separate criteria. BayesDel is not used (no verified published threshold available to this pipeline). Variant is missense, not synonymous, so BP7 is not applicable and is not separately invoked.

Rule

generic_acmg_pp3_bp4_revel_spliceai

Evidence considered

• REVEL score = 0.101 for NM_015559.2:c.575A>G (NP_056374.2:p.His192Arg), local REVEL v1.3 lookup; at or below the ClinGen SVI-calibrated BP4 threshold of <=0.290 (Pejaver et al. 2022, PMID 36413997), supporting BP4.
• SpliceAI Lookup evidence_sentence: 'SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03)'; source_data.spliceai_scores DS_AG=0.005, DS_AL=0.028, DS_DG=0.004, DS_DL=0.0, well below the 0.2 actionable-splice threshold, supporting no splice disruption and consistent with BP4.
• BayesDel score = -0.285904 present but not used to support BP4: no verified published threshold/citation available to this pipeline for BayesDel.

Still missing

• No gene-specific VCEP PP3/BP4 point-based lookup for SETBP1 to confirm generic threshold applicability

Sources

Reasoning

Cancerhotspots.org was queried directly for SETBP1 H192 and returned no result, with the pipeline's own evidence_sentence stating this variant does not lie in a statistically significant hotspot. No cspec/VCEP domain framework was found for SETBP1 (cspec.found=false, vcep_materials.json note='no cspec url available'), and no functional-domain annotation for residue 192 was retrieved anywhere in the case bundle. Without any positive hotspot or critical-domain evidence, and with an explicit negative hotspot check, PM1 is not met.

Evidence considered

• cancerhotspots.org query for 'SETBP1 H192' returned search_status='no_result' with evidence_sentence stating the variant does not lie in a statistically significant hotspot (embedded in evidence.json, no corresponding source_registry key available for direct citation).
• pvs1_gene_context.json germline literature review describes SETBP1 germline disease mechanisms as either loss-of-function (SETBP1 haploinsufficiency disorder/ADR29, via truncating variants) or a narrow gain-of-function missense hotspot (Schinzel-Giedion syndrome degron region); residue 192 is not indicated as part of any described hotspot or domain in the retrieved literature.
• No cspec/VCEP-defined critical domain boundaries were available (cspec.found=false; vcep_materials.json note='no cspec url available').

Still missing

• No structured functional-domain map (e.g. PSSD/SKI-homologous or repeat-region boundaries) for SETBP1 residue 192 was retrieved to fully rule out a critical domain location; only an absence of hotspot signal and absence of domain evidence were available.

Sources

Reasoning

PM2 is not met because the variant is present in population databases. It is observed in gnomAD v4.1 (164/1,613,884 alleles; two homozygotes), gnomAD v2.1 (58/250,366 alleles), and gnomAD-Canada (4/18,420 alleles). Although rare, it is not absent from controls.

Rule

Generic ACMG/AMP PM2: variant is absent from population databases or present at an appropriately rare frequency, subject to the applicable specification; this variant is observed in multiple population databases.

Evidence considered

• gnomAD v4.1 detects the variant at AF 0.000101618 with 164 alternate alleles and two homozygotes.
• gnomAD v2.1 detects the variant at AF 0.000231661 with 58 alternate alleles and no homozygotes.
• gnomAD-Canada detects the variant at AF 0.000217155 with 4 alternate alleles and no homozygotes.

Sources

Reasoning

No ClinGen VCEP is established for SETBP1 (cspec.found=false, vcep_materials note='no cspec url available', framework_mode=generic_acmg), so generic ACMG/AMP with published calibrated thresholds applies. The variant is a missense substitution (NP_056374.2:p.(His192Arg)). REVEL score is 0.101, well below the calibrated pathogenic-supporting threshold (REVEL>=0.644) from the ClinGen SVI-endorsed calibration (Pejaver et al., PMID 36413997), so REVEL does not support PP3. SpliceAI predicts no meaningful splice disruption (max delta score = 0.028, all DS_ sub-scores <0.03), far below the standard 0.2 SpliceAI actionability threshold, so the splice-impact path also does not support PP3. BayesDel score (-0.285904) is available but this pipeline has no verified published calibration/citation for a BayesDel PP3/BP4 threshold, so it is treated as not_available and not used to support or oppose PP3, consistent with policy for uncited predictor thresholds.

Rule

generic_acmg_pp3_bp4_revel_spliceai

Evidence considered

• REVEL score = 0.101 for NM_015559.2:c.575A>G (NP_056374.2:p.His192Arg), local REVEL v1.3 lookup; below the ClinGen SVI-calibrated PP3 threshold of >=0.644 (Pejaver et al. 2022, PMID 36413997), so does not meet PP3.
• SpliceAI Lookup: 'SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03)'; DS_AG=0.005, DS_AL=0.028, DS_DG=0.004, DS_DL=0.0 — all far below the 0.2 actionable-splice threshold, so the splice-impact path does not support PP3.
• BayesDel score = -0.285904 present in prefetch/source_registry but withheld from PP3 adjudication: no verified published threshold/citation available to this pipeline for BayesDel.

Still missing

• No gene-specific VCEP PP3/BP4 lookup table available for SETBP1 to cross-check generic REVEL/SpliceAI calls
• BayesDel score present but excluded from PP3/BP4 adjudication because no named, citable publication with a verified threshold is available to this pipeline

Sources

Reasoning

BA1 is not met. The variant is present at an overall allele frequency of 0.000101618 (164/1,613,884 alleles) in gnomAD v4.1, with the highest reported subpopulation frequency of 0.001636 (149/91,076 South Asian alleles), and at 0.000231661 overall in gnomAD v2.1. These frequencies are far below a stand-alone benign frequency threshold of 5%.

Rule

Generic ACMG/AMP BA1: allele frequency is greater than 5% in a population database.

Evidence considered

• gnomAD v4.1 reports 164 alternate alleles among 1,613,884 total alleles (AF 0.000101618), two homozygotes, and a maximum population AF of 0.001636 in South Asians.
• gnomAD v2.1 reports 58 alternate alleles among 250,366 alleles (AF 0.000231661), no homozygotes, and a maximum South Asian AF of 0.00186396.
• The observed frequencies do not approach the generic ACMG/AMP BA1 stand-alone benign threshold of 5%.

Sources

Reasoning

No cspec/VCEP was found for SETBP1 (cspec.found=false), and no artifact in the case bundle identifies an alternate nucleotide change producing the identical amino acid substitution p.(His192Arg) with an established pathogenic classification. pm5_candidates.json (which harvests same-residue comparators) explicitly declined automatic candidate collection, so no same-amino-acid-change comparator data is available.

Evidence considered

• pm5_candidates.json reports pm5_mode='unknown', eligible_for_classic_pm5_search=false, and zero candidates collected, so no same-residue/same-amino-acid comparator data exists in this case bundle to support or refute PS1.

Still missing

• No comparator variant search for other codon changes producing the identical p.(His192Arg) substitution was performed or returned in this case's evidence artifacts.

Sources

Reasoning

No proband-level de novo observation or confirmed parental testing is documented in the case-evidence bundle. The available records do not establish that the variant is absent from both biological parents, nor do they provide maternity/paternity, sequencing methodology, mosaicism assessment, or phenotype context.

Rule

Generic ACMG/AMP PS2 requires a confirmed de novo variant in an affected individual with confirmed parentage; strength depends on the quality and completeness of de novo evidence.

Evidence considered

• The case summary identifies a generic ACMG fallback because no SETBP1-specific framework was found.
• The consolidated case-evidence bundle contains no proband, parental testing, de novo, or maternity/paternity evidence for NM_015559.2:c.575A>G.
• Variant presence in population databases and ClinVar submissions does not establish de novo status and was not used for PS2.

Still missing

• Documented proband phenotype and indication
• Confirmed biological parentage
• Parental genotypes showing absence of NM_015559.2:c.575A>G in both parents
• Testing method, coverage, allele fractions, and assessment for parental mosaicism

Sources

Reasoning

No functional/biochemical assay data (e.g. protein stability, degradation, kinase activity, transcriptional activity, cell-based or biochemical complementation studies) for NM_015559.2:c.575A>G (p.His192Arg) in SETBP1 was found in the case bundle. No ClinGen VCEP specification exists for SETBP1 (cspec.found=false, gene_vcep_dir=null), so no VCEP-defined validated assay applies. The two literature hits associated with this case are the ACMG/AMP interpretation standards paper (PMID:25741868) and the Sherloc refinement paper (PMID:28492532), both general methodology references cited by ClinVar submitters, not variant-specific functional studies. OncoKB explicitly reports no variant-specific reviewed functional evidence for this substitution. Other retrieved SETBP1 literature (gene expression/TF-activity landscape paper, a nonsense-variant case report) does not describe a functional assay of this exact missense variant.

Evidence considered

• OncoKB evidence_sentence states no variant-specific reviewed functional evidence was identified for this variant.
• case_summary.json cspec.found is false and review_manifest.json gene_vcep_dir is null, confirming no SETBP1 VCEP specification is available to define a validated PS3/BS3 assay.
• The only PMIDs tied to this case (25741868, 28492532) are general ACMG/AMP and Sherloc methodology papers cited by ClinVar submitters, not variant-specific functional assay reports.

Still missing

• No published functional/biochemical assay (e.g. degradation, SKP2-binding, protein stability, transcriptional activity) has been performed on p.His192Arg specifically.
• No VCEP-approved PS3/BS3 assay framework exists for SETBP1.

Reasoning

No case-control enrichment dataset, affected-case count, control count, odds ratio, or statistically interpretable phenotype prevalence evidence for NM_015559.2:c.575A>G (SETBP1 p.His192Arg) is present in the evidence bundle.

Rule

Generic ACMG/AMP PS4 requires statistically significant enrichment in affected individuals compared with controls; no applicable SETBP1-specific framework was available.

Still missing

• A case-control study or adequately documented affected-case series with an appropriate control comparison is required to assess PS4.

Reasoning

No applicable SETBP1-specific VCEP framework was retrieved, so the generic ACMG/AMP rule applies. PM3 requires the evaluated variant to be observed in trans with a pathogenic or likely pathogenic variant in an affected individual, with strength based on the number and quality of such observations. The case-evidence bundle contains no affected-proband genotype, second pathogenic-variant identity, parental testing, phase determination, or inheritance information for NM_015559.2:c.575A>G (p.His192Arg). Therefore PM3 cannot be adjudicated.

Rule

generic ACMG/AMP PM3: pathogenic or likely pathogenic variant observed in trans in an affected individual; strength depends on the number and quality of observations

Evidence considered

• The retrieved framework materials state that no SETBP1-specific VCEP specification was found and that generic ACMG/AMP 2015 is the fallback.
• Review of the consolidated case-evidence bundle found no case-level family, affected-proband, compound-heterozygous, pathogenic-in-trans, phase, parental, or inheritance data for this variant.

Still missing

• Affected-proband observations involving NM_015559.2:c.575A>G
• A pathogenic or likely pathogenic allele in the same individual
• Experimental or parental evidence establishing trans phase
• Relevant inheritance mode and phenotype context

Sources

Reasoning

pm5_candidates.json explicitly reports eligible_for_classic_pm5_search=false with reason 'Unable to confirm classic same-residue PM5 semantics safely; skipping automatic candidate harvesting', and lists zero candidates. No alternate pathogenic missense change at codon 192 (e.g. p.His192Gln, p.His192Tyr, etc.) was identified anywhere in the case bundle, so PM5 cannot be assessed.

Evidence considered

• pm5_candidates.json recommendation.level='not_applicable' and hermes_instruction states not to apply PM5 from this artifact alone; candidate_summary shows total_candidates_seen=0, same_residue_candidates=0.

Still missing

• No same-residue alternate-amino-acid comparator variants (with their ClinVar classifications) were harvested or reviewed for codon 192 of SETBP1.

Sources

Reasoning

No credible de novo occurrence without confirmed parental testing is documented for this variant. The case bundle provides no affected proband observation linked to this variant and no evidence addressing whether either parent carries it.

Rule

Generic ACMG/AMP PM6 is considered for a presumed de novo event in an affected individual when parentage is established but parental testing is unavailable or incomplete; it must not be inferred from absence of family data alone.

Evidence considered

• The consolidated case-evidence bundle contains no case report, pedigree, proband phenotype, or parental-genotype information supporting a presumed de novo event.
• The available ClinVar and population-database records do not provide PM6-eligible family-level evidence and were not used to infer de novo status.

Still missing

• A documented affected proband carrying the variant
• Evidence that the variant was not detected in both parents despite incomplete or unreported parental testing
• Parentage and testing-method details
• Assessment for parental mosaicism

Sources

Reasoning

No family history, affected relatives, genotypes, phenotype segregation, or informative meioses are provided. Therefore, co-segregation of NM_015559.2:c.575A>G with a relevant SETBP1-related phenotype cannot be evaluated.

Rule

Generic ACMG/AMP PP1 requires co-segregation with disease in multiple affected family members; strength may increase with multiple informative meioses, but no segregation evidence is available here.

Evidence considered

• The consolidated case-evidence bundle contains no segregation table, pedigree, familial variant testing, affected-relative data, or meiosis count.
• The literature pass did not identify a variant-specific segregation publication; no paper was used for PP1.

Still missing

• Pedigree and family-history information
• Phenotype status of each informative relative
• Variant genotypes for affected and unaffected relatives
• Number of informative meioses and segregation results

Sources

Reasoning

PP2 requires the gene to have a low rate of benign missense variation and missense as a common mechanism of disease. No gnomAD missense constraint metric (missense Z-score/o-e ratio) is present anywhere in the case bundle, and no cspec/VCEP gene-level statement on missense constraint was found (cspec.found=false). The germline literature retrieved for SETBP1 (pvs1_gene_context.json) indicates a mixed gene mechanism: SETBP1 haploinsufficiency disorder is driven by loss-of-function/truncating variants, while Schinzel-Giedion syndrome is driven by a narrow gain-of-function missense hotspot, which does not clearly establish 'missense is a common mechanism of disease' in the generic PP2 sense across the whole gene. Without a missense constraint statistic or an authoritative gene-level statement, PP2 cannot be reliably assessed.

Evidence considered

• pvs1_gene_context.json literature review found SETBP1 germline disease mechanisms split between loss-of-function (SETBP1-HD/ADR29, truncating variants) and a narrow gain-of-function missense hotspot (Schinzel-Giedion syndrome), which does not unambiguously satisfy the PP2 'missense is a common disease mechanism across the gene' pattern.
• No missense constraint metric (Z-score/o-e) for SETBP1 is present in any retrieved artifact in this case bundle.

Still missing

• No gnomAD/ExAC missense constraint (Z-score or observed/expected ratio) for SETBP1 was retrieved.
• No cspec/VCEP statement on SETBP1 missense mechanism/benign missense rate was available.

Sources

Reasoning

The bundle does not provide clinical phenotype findings for the tested individual or a sufficiently specific SETBP1-related phenotype assessment. Gene-level disease descriptions and unrelated literature triage cannot establish PP4 for this exact variant.

Rule

Generic ACMG/AMP PP4 requires the patient's phenotype or highly specific clinical findings to be highly specific for a disease with a single-gene etiology; no applicable SETBP1-specific framework was available.

Still missing

• Patient-level phenotype information and a phenotype-specificity assessment for a disorder attributable to SETBP1 are required to assess PP4.

Reasoning

ClinVar contains an exact-variant match for NM_015559.2:c.575A>G / p.His192Arg, but the audit reports zero expert-panel submissions. The available benign and likely-benign assertions are ordinary single-submitter or clinical-laboratory submissions and therefore cannot trigger PP5.

Rule

Apply PP5 only when an exact-variant ClinVar expert panel classifies the variant as Pathogenic or Likely pathogenic; no such expert-panel assertion is present.

Evidence considered

• The exact ClinVar variation record is 1237167 for NM_015559.3(SETBP1):c.575A>G (p.His192Arg).
• ClinVar submission audit: expert_panel_submissions = 0; submissions are single-submitter or clinical-testing assertions, with aggregate labels of Likely benign and Benign.
• Ordinary laboratory submissions, aggregate ClinVar labels, and non-expert assertions were excluded from PP5 as instructed.

Still missing

• An exact-variant ClinVar expert-panel classification of Pathogenic or Likely pathogenic would be required for PP5 under the instructed rule.

Sources

Reasoning

BS1 cannot be adjudicated from the available evidence. The variant is observed at low frequency overall but reaches 0.001636 in the South Asian population in gnomAD v4.1 and 0.002937 in the smaller gnomAD-Canada South Asian subgroup. No SETBP1-specific VCEP framework, disease prevalence, penetrance estimate, or validated maximum credible allele-frequency threshold is available to determine whether this frequency is too high for a pathogenic SETBP1-related disorder.

Rule

Generic ACMG/AMP BS1: allele frequency is greater than expected for a disorder, requiring a disease- and gene-appropriate expected maximum frequency.

Evidence considered

• gnomAD v4.1 reports overall AF 0.000101618 and South Asian AF 0.001636 (149/91,076 alleles).
• gnomAD-Canada reports overall AF 0.000217155 (4/18,420 alleles) and South Asian AF 0.00293686 (4/1,362 alleles); the subgroup estimate is based on only four alternate alleles.
• No applicable SETBP1-specific VCEP specification was retrieved, and no disease-prevalence/penetrance-based frequency threshold was provided in the case bundle.

Still missing

• A disease-specific maximum credible allele-frequency threshold incorporating SETBP1-related disorder prevalence and penetrance is unavailable.
• The clinical phenotype and ascertainment status of the population-database carriers are not available for BS1 adjudication.

Sources

Reasoning

BS2 cannot be adjudicated. gnomAD v4.1 reports two homozygotes (both in the South Asian population), but the bundle does not establish that these individuals were phenotypically healthy, that SETBP1-related disease is sufficiently penetrant for this observation to be informative, or that the variant's disease mechanism makes homozygosity relevant. Population-database presence alone is insufficient to establish BS2.

Rule

Generic ACMG/AMP BS2: observation of the variant in a healthy adult or healthy adults, including in the homozygous state when appropriate for the disorder.

Evidence considered

• gnomAD v4.1 reports two homozygotes among 1,613,884 alleles; both are reported within the South Asian population (149 alternate alleles, 2 homozygotes).
• gnomAD v2.1 and gnomAD-Canada report zero homozygotes.
• The available database records do not provide individual-level phenotype, health-status, or ascertainment information for the homozygotes.

Still missing

• No phenotype or clinical ascertainment data are available for the two gnomAD v4.1 homozygotes.
• SETBP1-related disorder penetrance and the disease-mechanism assumptions needed to interpret homozygotes are not specified for this case.

Sources

Reasoning

No functional/biochemical assay data demonstrating normal (wild-type-like) function for NM_015559.2:c.575A>G (p.His192Arg) in SETBP1 was found in the case bundle. No ClinGen VCEP specification exists for SETBP1, so no validated assay/threshold for a benign functional impact call applies. The available literature is limited to general ACMG/AMP and Sherloc methodology papers, not a functional characterization of this variant.

Evidence considered

• OncoKB evidence_sentence states no variant-specific reviewed functional evidence was identified for this variant.
• case_summary.json cspec.found is false and review_manifest.json gene_vcep_dir is null, confirming no SETBP1 VCEP specification is available.

Still missing

• No published functional assay showing normal/wild-type activity for p.His192Arg is available.
• No VCEP-approved PS3/BS3 assay framework exists for SETBP1.

Reasoning

No unaffected relatives known to carry the variant, no phenotype discordance analysis, and no non-segregation study are documented. The available population frequency and ClinVar classification data cannot establish lack of segregation within a disease family.

Rule

Generic ACMG/AMP BS4 requires lack of segregation with disease in affected family members or presence in unaffected relatives in a manner inconsistent with the disease model; it cannot be assigned without informative family data.

Evidence considered

• The consolidated case-evidence bundle contains no family-level non-segregation or phenotype-discordance evidence for NM_015559.2:c.575A>G.
• Population observations and aggregate ClinVar submissions were not treated as BS4 evidence because BS4 requires family-based non-segregation evidence.

Still missing

• A defined family with a relevant phenotype
• Genotypes and phenotype assessments for informative unaffected relatives
• Evidence that the variant fails to segregate with disease after accounting for age-dependent penetrance and phenocopies

Sources

Reasoning

BP1 applies when a gene's disease mechanism is primarily truncating/loss-of-function such that missense variants are not expected to be disease-causing. pvs1_gene_context.json germline literature review supports a loss-of-function mechanism for SETBP1 haploinsufficiency disorder (via truncating variants), but SETBP1 also has a well-documented, disease-relevant gain-of-function missense mechanism (Schinzel-Giedion syndrome degron hotspot, and somatic myeloid-malignancy hotspot mutations referenced in the retrieved literature), meaning missense variants ARE an established mechanism of disease for this gene in a different clinical context. Because the case bundle does not specify which SETBP1-associated condition is under evaluation and does not provide a cspec/VCEP statement resolving this dual mechanism, BP1 cannot be safely applied or excluded.

Evidence considered

• pvs1_gene_context.json literature review found supporting papers describing SETBP1 haploinsufficiency disorder (ADR29) caused by loss-of-function/truncating variants (e.g. PMID:38585550 describes a nonsense variant p.(Gln178*) classified pathogenic for this LOF-driven condition) alongside a distinct gain-of-function missense-driven condition (Schinzel-Giedion syndrome) and somatic missense-driven hematologic malignancy mechanisms, indicating missense variants are an established disease mechanism for SETBP1 in other contexts, precluding straightforward BP1 application.

Still missing

• No cspec/VCEP guidance clarifying whether BP1 applies to SETBP1 missense variants outside the known gain-of-function hotspot.
• No case-specific indication of which SETBP1-associated condition (haploinsufficiency disorder vs. Schinzel-Giedion syndrome) is being evaluated, which is needed to determine if the gene's truncating-predominant mechanism applies to this variant's clinical context.

Sources

Reasoning

No applicable SETBP1-specific VCEP framework was retrieved, so the generic ACMG/AMP rule applies. BP2 requires an appropriate phase relationship between the evaluated variant and a pathogenic or likely pathogenic variant—typically trans observation for a dominant disorder or cis observation for a recessive disorder. The case-evidence bundle provides no individual-level genotype data, pathogenic comparator allele, phase information, affected/unaffected status, or confirmed inheritance model. The available population observations and ClinVar classifications do not establish BP2. Therefore BP2 cannot be adjudicated.

Rule

generic ACMG/AMP BP2: variant observed in trans with a pathogenic or likely pathogenic variant for a dominant disorder, or in cis with a pathogenic or likely pathogenic variant for a recessive disorder

Evidence considered

• The retrieved framework materials state that no SETBP1-specific VCEP specification was found and that generic ACMG/AMP 2015 is the fallback.
• Review of the consolidated case-evidence bundle found no case-level allelic, family, phase, parental, or inheritance data that could support BP2; population frequency and variant-level database classifications are not phase evidence.

Still missing

• A pathogenic or likely pathogenic comparator allele in the same individual
• Reliable cis/trans phase determination
• Affected/unaffected phenotype and inheritance context
• Confirmation of the disease inheritance model relevant to BP2

Sources

Reasoning

The evidence bundle contains no documented alternate molecular diagnosis in the patient and no evidence that the patient's phenotype is explained by another pathogenic variant or molecular cause. The exact-variant ClinVar benign assertions cannot establish BP5.

Rule

Generic ACMG/AMP BP5 requires an alternate molecular basis that explains the patient's phenotype; no such case evidence is available.

Still missing

• A documented alternate molecular basis that explains the patient's phenotype is required to assess BP5.

Reasoning

ClinVar contains an exact-variant match with Benign and Likely benign laboratory assertions, but the audit reports zero expert-panel submissions. Because no exact-variant ClinVar expert-panel classification of Benign or Likely benign is present, BP6 cannot be applied.

Rule

Apply BP6 only when an exact-variant ClinVar expert panel classifies the variant as Benign or Likely benign; no such expert-panel assertion is present.

Evidence considered

• The exact ClinVar variation record is 1237167 for NM_015559.3(SETBP1):c.575A>G (p.His192Arg).
• ClinVar submission audit: expert_panel_submissions = 0; the available assertions are from non-expert clinical laboratories or single submitters.
• Aggregate ClinVar labels and non-expert assertions were excluded from BP6 as instructed.

Still missing

• An exact-variant ClinVar expert-panel classification of Benign or Likely benign would be required for BP6 under the instructed rule.

Sources