Criteria Specification Registry

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Criteria Specification

ClinGen Ocular Anterior Segment Disorder Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PAX6 Version 1.0

Type: Tavtigian et.al., 2020 - Bayesian adaptation of Richards et.al., 2015 Description : Rule specifications for curating variants in PAX6 (MANE NM_001368894.2, commonly referenced transcript NM_000280.6) and are associated with PAX6-related ocular dysgenesis.

Version : 1.0 DOI : 10.5281/zenodo.22115985

Ocular Anterior Segment Disorder VCEP

Released

8/26/2026

17:35:08

Contributors & Keywords

Research Group: Ocular Anterior Segment Disorder VCEP Rights Holder: The Clinical Genome Resource (ClinGen)

Keywords: human biology genomics variant variant classification clingen disease standards PAX6 NM_001368894.2 Autosomal dominant inheritance PAX6-related ocular dysgenesis

Rules for PAX6

Gene: PAX6 (HGNC:8620) HGNC Name: paired box 6 Transcripts: NM_001368894.2 Disease: PAX6-related ocular dysgenesis (MONDO:0800183) Mode of Inheritance: Autosomal dominant inheritance

Criteria & Strength Specifications
PVS1 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease. Caveats: • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7). • Use caution interpreting LOF variants at the extreme 3’ end of a gene. • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact. • Use caution in the presence of multiple transcripts. VCEP Specifications: The Ocular Anterior Segment Dysgenesis VCEP will utilize SVI’s PVS1 recommendation for determining applicable PVS1 strength level as well as using experimental splicing data to score non-canonical splice variants under the PVS1 code (Abou Tayoun et al 2018; PMID:30192042 and Walker et. al., PMID 37352859). The Ocular Anterior Segment Dysgenesis VCEP would like to highlight the reported impact of the PAX6 Downstream Regulatory Region (DRR) to PAX6 expression. The ClinGen Dosage Curation Working Group has curated the PAX6 DRR (11p13 PAX6 Downstream Regulatory Region (within introns 5-7 of ELP4); ISCA-46758) as having sufficient evidence of haploinsufficiency which is in line with clinical observations of PAX6-related ocular dysgenesis in cases where the minimum deletion region chr11:31626701-31644792 (hg38) (PMID 30291432) which includes intron 7 to exon 9 of ELP4 which is approximately 180kb 3’ of PAX6. Extension variants will be curated under PVS1 to recognize the evidence of this variant type leading to PAX6-related ocular dysgenesis in at least 21 families and shown to segregate with aniridia in at least 3 families (PMIDs 32360764, 32396632, 29618921, 26661695, 18483559, 22361317, 21850189, 35791194, 36816037) Splice impacting variants in exons 2 and 3 of the 5' UTR may be scored under PVS1 if there is a predicted impact to splicing due to disruption of a canonical splice site OR experimental evidence of altered splicing OR evidence of reduced expression to ≤50% of wildtype (See Filatova et. al., PMID 34174135) Stand Alone Very Strong The Ocular Anterior Segment Dysgenesis will utilize SVI’s PVS1 recommendation for determining applicable PVS1 strength level (Abou Tayoun et al 2018; PMID:30192042). See modified decision was modified for PAX6. Default Point Value: 8 Modification Type: Gene-specific Strong The Ocular Anterior Segment Dysgenesis will utilize SVI’s PVS1 recommendation for determining applicable PVS1 strength level (Abou Tayoun et al 2018; PMID:30192042). See modified decision was modified for PAX6. Default Point Value: 4 Modification Type: Gene-specific Moderate The Ocular Anterior Segment Dysgenesis will utilize SVI’s PVS1 recommendation for determining applicable PVS1 strength level (Abou Tayoun et al 2018; PMID:30192042). See modified decision was modified for PAX6. Default Point Value: 2 Modification Type: Gene-specific Supporting The Ocular Anterior Segment Dysgenesis will utilize SVI’s PVS1 recommendation for determining applicable PVS1 strength level (Abou Tayoun et al 2018; PMID:30192042). See modified decision was modified for PAX6. Default Point Value: 1 Modification Type: Gene-specific Not Applicable
PS1 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. Example: Val->Leu caused by either G>C or G>T in the same codon. Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level. VCEP Specifications: PS1_Strength may be combined with PP3 or PVS1 following guidance in Walker et. al.; PMID 37352859 Stand Alone Very Strong Strong Missense variant at the same codon leading to the same amino acid substitution as a variant classified pathogenic by the OASD VCEP’s guidelines and has the same predicted impact to splicing Default Point Value: 4 Modification Type: Gene-specific Moderate Missense variant at the same codon leading to the same amino acid substitution as a variant classified likely pathogenic by the OASD VCEP’s guidelines and has the same predicted impact to splicing Default Point Value: 2 Modification Type: Gene-specific Supporting Follow guidance in Walker et. al.; PMID 37352859 for PS1_Strength in combination with PP3 or PVS1 Default Point Value: 1 Modification Type: Gene-specific Not Applicable
PS2 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity. VCEP Specifications: All de novo variants (confirmed AND unconfirmed parentage) should be scored under PS2 using the attached scoring and classification weight tables Phenotype highly specific for gene = aniridia OR foveal hypoplasia Phenotype consistent with gene but not highly specific = ≥ 2 of the following: Peters anomaly, cataracts, microphthalmia, nystagmus, optic disc anomalies Do not score if phenotype is unilateral and the other eye is described as normal or healthy Stand Alone Very Strong ≥ 4pts using the attached de novo scoring table Default Point Value: 8 Modification Type: Gene-specific Strong ≥2 pts using the attached de novo scoring table Default Point Value: 4 Modification Type: Gene-specific Moderate ≥1 pt using the attached de novo scoring table Default Point Value: 2 Modification Type: Gene-specific Supporting ≥0.5 pts using the attached de novo scoring table Default Point Value: 1 Modification Type: Gene-specific Not Applicable
PS3 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product. Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established. VCEP Specifications: The OASD VCEP will follow the SVI recommendations from Brnich et. al.; PMID 31892348 when assessing functional assays to apply PS3 toward functional evidence Stand Alone Very Strong Default Point Value: 8 Strong Mouse model with a variant reported in a human case with aniridia phenotype or mouse phenotype is similar to human disease (iris hypoplasia, abnormal, lens morphology, cataracts, corneal opacification, and incomplete separation of lens from the cornea. The genetic background of the animal HAS been assessed and off-target effects for models chemically/radiation‑induced or targeted mutations induced were assessed. Default Point Value: 4 Modification Type: Gene-specific Moderate Mouse model with a human mutation reported with aniridia phenotype or mouse phenotype is similar to human disease (must have 2 or more of these features: iris hypoplasia, abnormal, lens morphology, cataracts, corneal opacification, and incomplete separation of lens from the cornea, microphthalmia). PAX6 reduction in function assayed by luciferase assay AND binding activity to ≤50% of wildtype control Default Point Value: 2 Modification Type: Gene-specific Supporting Demonstrated decrease in PAX6 function by luciferase assay reduction must be ≤50% of wildtype control High-throughput assay assaying PAX6 paired domain DNA binding by yeast-1-hybrid competition assay (McDonnell et. al.; PMID 38849565) that reaches the pathogenic threshold set by the OASD VCEP Default Point Value: 1 Modification Type: Gene-specific Not Applicable
PS4 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance. Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence. VCEP Specifications: Use PS4 for counting probands from multiple independent studies. Probands clinical phenotype which either meets PP4_Supporting criteria OR has 2 or more of the following features Microphthalmia, corneal opacity, foveal hypoplasia, limbal stem cell deficiency, optic nerve anomalies, congenital or juvenile cataracts Do not apply this code unless BS1 is Not Met - Can not be the same case scored for PP4_[Strength] - Do not score if phenotype is unilateral and the other eye is described as normal or healthy Stand Alone Very Strong 17+ probands meeting the above phenotype criteria Default Point Value: 8 Modification Type: Gene-specific Strong 5-16 probands meeting the above phenotype criteria Default Point Value: 4 Modification Type: Gene-specific Moderate 3-4 probands meeting the above phenotype criteria Default Point Value: 2 Modification Type: Gene-specific Supporting 2 probands meeting the above phenotype criteria Default Point Value: 1 Modification Type: Gene-specific Not Applicable
PM1 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation. Stand Alone Very Strong Strong Default Point Value: 4 Moderate This code can be applied to a missense variant that occurs in the homeodomain (c.676 to c.841) or paired domain (c.10 to c.427) Do not apply this code if the variant meets BS1 Default Point Value: 2 Modification Type: Gene-specific Supporting Default Point Value: 1 Not Applicable
PM2 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium. Caveat: Population data for indels may be poorly called by next generation sequencing. Stand Alone Very Strong Strong Moderate Default Point Value: 2 Supporting Apply to variants with Popmax MAF ≤0.000001 (1x10^-6) allele frequency in the most recent version of gnomAD population database Population codes are NOT MET if both genomes and exomes fail gnomAD QC metrics Default Point Value: 1 Modification Type: Gene-specific Not Applicable
PM3 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary For recessive disorders, detected in trans with a pathogenic variant Note: This requires testing of parents (or offspring) to determine phase. Stand Alone Very Strong Default Point Value: 8 Strong Default Point Value: 4 Moderate Default Point Value: 2 Supporting Default Point Value: 1 Not Applicable Comments: This code is not applicable to PAX6
PM4 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants. VCEP Specifications: Use this code only for small in-frame indels, extension variants will be scored under PVS1 Stand Alone Very Strong Strong Default Point Value: 4 Moderate Protein length changes due to in-frame deletions/insertions in a non-repeat region Default Point Value: 2 Modification Type: Gene-specific Supporting Default Point Value: 1 Not Applicable
PM5 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before. Example: Arg156His is pathogenic; now you observe Arg156Cys. Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level. VCEP Specifications: Do not combine with PM1 - use this code preferentially to recognize the impact from the amino acid substitution specific to the variant under consideration Stand Alone Very Strong Strong Default Point Value: 4 Moderate Can be applied when: at least one variant at an amino acid residue previously curated pathogenic by the OASD VCEP leads to a different amino acid from the comparison variant at least two variants at an amino acid residue previously curated likely pathogenic by the OASD VCEP leads to a different amino acid from the comparison variant predicted impact to splicing should match the informative variant Default Point Value: 2 Modification Type: Gene-specific Supporting Can be applied when: one variant at an amino acid residue previously curated likely pathogenic by the OASD VCEP leads to a different amino acid from the comparison variant predicted impact to splicing should match the informative variant Default Point Value: 1 Modification Type: Gene-specific Not Applicable
PM6 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Assumed de novo, but without confirmation of paternity and maternity. VCEP Specifications: See PS2 criteria Stand Alone Very Strong Default Point Value: 8 Strong Default Point Value: 4 Moderate Default Point Value: 2 Supporting Default Point Value: 1 Not Applicable Comments: See PS2
PP1 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease. Note: May be used as stronger evidence with increasing segregation data. VCEP Specifications: Cases must present with aniridia OR foveal hypoplasia OR 2+ of the following features must be reported and not aniridia: Peters anomaly, cataracts, microphthalmia, foveal hypoplasia +/- nystagmus, optic disc anomalies +/- nystagmus - Do not score a family member if the phenotype is unilateral and the other eye is described as normal or healthy Stand Alone Very Strong Strong ≥7 meioses in ≥1 families Default Point Value: 4 Modification Type: Gene-specific Moderate ≥5 meioses in ≥1 families Default Point Value: 2 Modification Type: Gene-specific Supporting ≥ 3 meioses, in ≥1 families Default Point Value: 1 Modification Type: Gene-specific Not Applicable
PP2 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease. VCEP Specifications: Do not apply this code if there is evidence of a loss of function that meets evidence criteria for the PVS1 code OR has a SpliceAI score of >0.2 Stand Alone Very Strong Strong Moderate Supporting Default Point Value: 1 Not Applicable Comments: High constraint is limited to the paired and homeo domains which are critical to the function of PAX6 and not the entire coding sequence
PP3 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant. Stand Alone Very Strong Strong Default Point Value: 4 Moderate REVEL score of ≥0.9 Default Point Value: 2 Modification Type: Gene-specific Supporting REVEL score of 0.70 to 0.899 OR spliceAI ≥0.2 Default Point Value: 1 Modification Type: Gene-specific Not Applicable
PP4 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology. VCEP Specifications: This code is not applicable unless BS1 is NOT MET - Do not score if phenotype is unilateral and the other eye is described as normal or healthy Stand Alone Very Strong Strong Default Point Value: 4 Moderate Absence or partial absence of the iris (aniridia) AND 1 or more of the following: Foveal hypoplasia Limbal stem cell deficiency Optic nerve anomalies Congenital or juvenile cataracts Nystagmus Default Point Value: 2 Modification Type: Gene-specific Supporting Absence or partial absence of the iris (aniridia) OR ≥3 of the following phenotypes: foveal hypoplasia limbal stem cell deficiency optic nerve anomalies congenital or juvenile cataracts nystagmus Default Point Value: 1 Modification Type: Gene-specific Not Applicable
PP5
Original ACMG Summary Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation. Not Applicable This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. PubMed : 29543229
BA1 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium. Stand Alone Apply to variants with a Total Grpmax filtering allele frequency of ≥0.0001 in the most recent version of gnomAD population database - population codes are NOT MET if both genomes and exomes fail gnomAD QC metrics Default Point Value: Not Applicable Modification Type: Gene-specific Very Strong Strong Moderate Supporting Not Applicable
BS1 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Allele frequency is greater than expected for disorder. Stand Alone Very Strong Strong Apply to variants with a Total Grpmax filtering allele frequency of ≥0.00001 in the most recent version of gnomAD population database - population codes are NOT MET if both genomes and exomes fail gnomAD QC metrics Default Point Value: -4 Modification Type: Gene-specific Moderate Default Point Value: -2 Supporting Default Point Value: -1 Not Applicable
BS2 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age. VCEP Specifications: This code only applies to cases shown to carry the variant under consideration with no ocular phenotypes reported Stand Alone Very Strong Strong Apply to variants obvserved in the heterozygous state in an individual with a documented normal dilated ocular exam Default Point Value: -4 Modification Type: Gene-specific Moderate Apply to variants observed in the heterozygous state that is found in a reportedly unaffected case with no documentation of a dilated ocular exam Default Point Value: -2 Modification Type: Disease-specific Supporting Default Point Value: -1 Not Applicable
BS3 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing. Stand Alone Very Strong Strong Default Point Value: -4 Moderate Default Point Value: -2 Supporting Default Point Value: -1 Not Applicable
BS4 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Lack of segregation in affected members of a family. Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation. Stand Alone Very Strong Strong Apply if the variant under consideration is not found in a family member reported with phenotypes consistent with PP4 criteria Default Point Value: -4 Modification Type: Gene-specific Moderate Default Point Value: -2 Supporting Apply if the variant under consideration is not found in a family member with a phenotype consistent with the probands ocular phenotype Proband should not meet PP4 Default Point Value: -1 Modification Type: Gene-specific Not Applicable
BP1 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Missense variant in a gene for which primarily truncating variants are known to cause disease. Stand Alone Very Strong Strong Default Point Value: -4 Moderate Default Point Value: -2 Supporting Default Point Value: -1 Not Applicable
BP2 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern. Stand Alone Very Strong Strong Default Point Value: -4 Moderate Default Point Value: -2 Supporting Apply if the variant under consideration is found in addition to a second variant that has been curated as pathogenic/likely pathogenic using the OASD VCEPs PAX6 rule specifications Default Point Value: -1 Modification Type: Gene-specific Not Applicable
BP3 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary In frame-deletions/insertions in a repetitive region without a known function. Stand Alone Very Strong Strong Default Point Value: -4 Moderate Default Point Value: -2 Supporting Default Point Value: -1 Not Applicable
BP4 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc) Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant. Stand Alone Very Strong Strong Default Point Value: -4 Moderate Default Point Value: -2 Supporting Can be applied to missense variants with a REVEL score ≤0.29 AND SpliceAI ≤0.1 For other variant types SpliceAI ≤0.1 Default Point Value: -1 Modification Type: Gene-specific Not Applicable
BP5 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Variant found in a case with an alternate molecular basis for disease. Stand Alone Very Strong Strong Default Point Value: -4 Moderate Default Point Value: -2 Supporting Default Point Value: -1 Not Applicable
BP6
Original ACMG Summary Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation. Not Applicable This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. PubMed : 29543229
BP7 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved. Stand Alone Very Strong Strong Default Point Value: -4 Moderate Default Point Value: -2 Supporting Can be applied to synonymous variants as well as intronic variants beyond the +7/-21 splice region that also meet BP4 criteria. Conservation metrics are not required for scoring this code. Default Point Value: -1 Modification Type: Gene-specific Not Applicable

Point Based Variant Classification Categories

Category	Point Ranges
Pathogenic	10
Likely Pathogenic	6 - 9
Uncertain Significance	0 - 5
Likely Benign	-6 - -1
Benign	-7

Additional Notes :

Files & Images

PVS1 flow-chart:

Functional assay worksheet:

PS2 case scoring and classification weight tables: