Criteria Specification (CSpec) Registry is intended to provide access to the Criteria Specifications used and applied by ClinGen Variant Curation Expert Panels and biocurators in the classification of variants.
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| Criteria & Strength Specifications
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| PVS1 | ||||
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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:
Please reference ABCA4 Modified ClinGen SVI PVS1 flowchart below. Stand Alone
Very Strong
Please use the SVI WG decision tree modified for the ABCA4 gene.
Default Point Value:
8
Modification Type:
Gene-specific
Strong
Please use the SVI WG decision tree modified for the ABCA4 gene.
Default Point Value:
4
Modification Type:
Gene-specific
Moderate
Please use the SVI WG decision tree modified for the ABCA4 gene.
Default Point Value:
2
Modification Type:
Gene-specific
Supporting
Default Point Value:
1
Not Applicable
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| PS1 | ||||
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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. Stand Alone
Very Strong
Strong
Comparison missense variant must reach a pathogenic classification using the ABCA4 VCEP specifications. Do not apply if the comparison variant is suspected to cause a splicing defect via SpliceAI or other splice predictor. OR Comparison splicing variant must reach a pathogenic classification using the ABCA4 VCEP specifications and both variants must share the same predicted splicing effect. OR See Walker, et al 2023 (PMID: 37352859) Figure 5 to use this rule code for variants with RNA sequencing data.
Default Point Value:
4
Modification Type:
General recommendation
Moderate
Comparison variant must reach a likely pathogenic classification using the ABCA4 VCEP specifications. Do not apply if the comparison variant is suspected to cause a splicing defect via SpliceAI or other splice predictor. OR Comparison splicing variant must reach a likely pathogenic classification using the ABCA4 VCEP specifications and both variants must share the same predicted splicing effect. OR See Walker, et al 2023 (PMID: 37352859) Figure 5 to use this rule code for variants with RNA sequencing data.
Default Point Value:
2
Modification Type:
General recommendation
Supporting
See Walker, et al 2023 (PMID: 37352859) Figure 5 to use this rule code for variants with RNA sequencing data.
Default Point Value:
1
Modification Type:
General recommendation
Not Applicable
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| PS2 | ||||
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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:
Probands must have a second ABCA4 variant that is classified using the ABCA4 VCEP Rule Classification Guidelines to use this rule code. If the second ABCA4 variant is classified as a variant of uncertain significance (VUS), the proband’s points should be downgraded by half. Additionally, this code’s strength should be capped at moderate if phase is unknown for all probands. See additional guidance below. Stand Alone
Very Strong
Use proposed SVI point recommendations for “Phenotype consistent with gene but not highly specific” for probands with Stargardt disease. Use proposed SVI point recommendations for “Phenotype consistent with gene but not highly specific and high genetic heterogeneity” for probands with other ABCA4-related retinopathies (e.g. - retinitis pigmentosa, cone-rod dystrophy, etc.).
Default Point Value:
8
Modification Type:
Disease-specific
Strong
Use proposed SVI point recommendations for “Phenotype consistent with gene but not highly specific” for probands with Stargardt disease. Use proposed SVI point recommendations for “Phenotype consistent with gene but not highly specific and high genetic heterogeneity” for probands with other ABCA4-related retinopathies (e.g. - retinitis pigmentosa, cone-rod dystrophy, etc.).
Default Point Value:
4
Modification Type:
Disease-specific
Moderate
Use proposed SVI point recommendations for “Phenotype consistent with gene but not highly specific” for probands with Stargardt disease. Use proposed SVI point recommendations for “Phenotype consistent with gene but not highly specific and high genetic heterogeneity” for probands with other ABCA4-related retinopathies (e.g. - retinitis pigmentosa, cone-rod dystrophy, etc.).
Default Point Value:
2
Modification Type:
Disease-specific
Supporting
Use proposed SVI point recommendations for “Phenotype consistent with gene but not highly specific” for probands with Stargardt disease. Use proposed SVI point recommendations for “Phenotype consistent with gene but not highly specific and high genetic heterogeneity” for probands with other ABCA4-related retinopathies (e.g. - retinitis pigmentosa, cone-rod dystrophy, etc.).
Default Point Value:
1
Modification Type:
Disease-specific
Not Applicable
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| PS3 | ||||
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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. Stand Alone
Very Strong
Default Point Value:
8
Strong
Loss of function of ABCA4 protein in transgenic mice measured by autofluorescence and/or A2E production.
Default Point Value:
4
Modification Type:
Disease-specific
Moderate
Default Point Value:
2
Supporting
Measurement of ABCA4 expression or ATPase activity in HEK293 or HeLa cells. See list of approved functional assays in PS3/BS3 Guidance spreadsheet below.
Default Point Value:
1
Modification Type:
Disease-specific
Not Applicable
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| PS4 | ||||
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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. Stand Alone
Very Strong
Default Point Value:
8
Strong
Enrichment analysis was performed for all likely bi-allelic ABCA4 variants that were published up to December 31, 2020 compared to population matched gnomAD data from Cornelis et al., 20221. This code can be applied to variants with an OR > or = 5, where the CI does not contain 1.
Default Point Value:
4
Modification Type:
Disease-specific
Moderate
Enrichment analysis was performed for all likely bi-allelic ABCA4 variants that were published up to December 31, 2020 compared to population matched gnomAD data from Cornelis et al., 20221. This code can be applied to variants with an OR greater or equal to 3 and less than 5, where the CI does not contain 1.
Default Point Value:
2
Modification Type:
Disease-specific
Supporting
Default Point Value:
1
Not Applicable
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| PM1 | ||||
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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
Default Point Value:
2
Supporting
Default Point Value:
1
Not Applicable
Comments:
This code is not applicable as there is benign variation throughout the ABCA4 gene.
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| PM2 | ||||
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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
Total MAF <0.0001 in gnomAD.
Default Point Value:
1
Modification Type:
Disease-specific
Not Applicable
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| PM3 | ||||
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Original ACMG Summary
For recessive disorders, detected in trans with a pathogenic variant
Note: This requires testing of parents (or offspring) to determine phase.
VCEP Specifications:
Neither variant can meet BS1 or BA1 criteria to apply this code. Stand Alone
Very Strong
Use proposed SVI point recommendations. Both variants must be classified using ABCA4 Rule Specifications.
Default Point Value:
8
Modification Type:
General recommendation
Strong
Use proposed SVI point recommendations. Both variants must be classified using ABCA4 Rule Specifications.
Default Point Value:
4
Modification Type:
General recommendation
Moderate
Use proposed SVI point recommendations. Both variants must be classified using ABCA4 Rule Specifications.
Default Point Value:
2
Modification Type:
General recommendation
Supporting
Use proposed SVI point recommendations. Both variants must be classified using ABCA4 Rule Specifications.
Default Point Value:
1
Modification Type:
General recommendation
Not Applicable
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| PM4 | ||||
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Original ACMG Summary
Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.
Stand Alone
Very Strong
Strong
Default Point Value:
4
Moderate
This code can be applied for >1 amino acid deletion/insertion or a stop loss variant, or >1 nucleotide with PhyloP ≥7.367 (https://www.medrxiv.org/content/10.1101/2023.04.24.23288782v1).
Default Point Value:
2
Modification Type:
Gene-specific
Supporting
This code can be applied for 1 amino acid deletion/insertion or a stop loss variant, or 1 nucleotide with PhyloP ≥7.367 (https://www.medrxiv.org/content/10.1101/2023.04.24.23288782v1).
Default Point Value:
1
Modification Type:
Gene-specific
Not Applicable
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| PM5 | ||||
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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. Stand Alone
Very Strong
Strong
Default Point Value:
4
Moderate
Comparison variant must reach a pathogenic classification using the ABCA4 VCEP specifications. Do not apply if the comparison variant is suspected to cause a splicing defect via SpliceAI or other splice predictor.
Default Point Value:
2
Modification Type:
General recommendation
Supporting
Comparison variant must reach a likely pathogenic classification using the ABCA4 VCEP specifications. Do not apply if the comparison variant is suspected to cause a splicing defect via SpliceAI or other splice predictor.
Default Point Value:
1
Modification Type:
General recommendation
Not Applicable
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| PM6 | ||||
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Original ACMG Summary
Assumed de novo, but without confirmation of paternity and maternity.
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:
Use the PS2 code for all (including non-confirmed paternity) de novo variants.
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| PP1 | ||||
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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:
Please note: Non-truncating in trans variants must be curated using the ClinGen ABCA4 VCEP Rule Specifications and reach a pathogenic or likely pathogenic classification. Truncating in trans variants need no further curation. Stand Alone
Very Strong
Strong
Segregations in proband plus >2 affected relatives.
Default Point Value:
4
Modification Type:
Disease-specific
Moderate
Segregation in proband plus 2 affected relatives.
Default Point Value:
2
Modification Type:
Disease-specific
Supporting
Segregation in proband plus 1 affected relative.
Default Point Value:
1
Modification Type:
Disease-specific
Not Applicable
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| PP2 | ||||
|
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.
Stand Alone
Very Strong
Strong
Moderate
Supporting
Default Point Value:
1
Not Applicable
Comments:
This rule does not apply because this gene is not constrained for missense variation.
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| PP3 | ||||
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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
This code is applicable for missense variants with a REVEL score of >0.772 or for synonymous or indel variants with a CADD score of greater or equal to 28.1 (https://www.medrxiv.org/content/10.1101/2023.04.24.23288782v1). This code is also applicable for variant with a SpliceAI score of greater than or equal to 0.8.
Default Point Value:
2
Modification Type:
General recommendation,Gene-specific
Supporting
This code is applicable for missense variants with a REVEL score between 0.644-0.772 or for synonymous or indel variants with a CADD score between 25.3-28.0 (https://www.medrxiv.org/content/10.1101/2023.04.24.23288782v1). This code is also applicable for variant with a SpliceAI score of greater than or equal to 0.2.
Default Point Value:
1
Modification Type:
General recommendation,Gene-specific
Not Applicable
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| PP4 | ||||
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Original ACMG Summary
Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.
VCEP Specifications:
Use the ABCA4 PP4 Specification Table attached below for the list of phenotypic and genetic testing criteria available for scoring a single proband. This rule is not applicable for variants meeting BS1 or BA1 criteria. Stand Alone
Very Strong
Strong
Default Point Value:
4
Moderate
This code is applicable when a single proband can be awarded 8 or more phenotype points.
Default Point Value:
2
Modification Type:
Disease-specific
Supporting
This code is applicable when a single proband can be awarded 3-7.5 phenotype points.
Default Point Value:
1
Modification Type:
Disease-specific
Not Applicable
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| 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
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| BA1 | ||||
|
Original ACMG Summary
Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
Stand Alone
Gprmax allele frequency cutoff of greater than 0.163 in gnomAD.
Default Point Value:
Not Applicable
Modification Type:
Disease-specific
Very Strong
Strong
Moderate
Supporting
Not Applicable
Comments:
Minor allele frequency cutoff of greater than 0.163 in gnomAD.
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| BS1 | ||||
|
Original ACMG Summary
Allele frequency is greater than expected for disorder.
VCEP Specifications:
The BS1 rule is based on the Whiffen-Ware calculator using a prevalence of 1 in 7,500, allelic and gene heterogeneity of 1 and penetrance of 0.5. The following variants are excluded from this rule code (or see attached list below): The following variants are excluded from this rule code (or see list below):
Stand Alone
Very Strong
Strong
Grpmax allele frequency cutoff of greater than 0.0163 in gnomAD.
Default Point Value:
-4
Modification Type:
Disease-specific
Moderate
Default Point Value:
-2
Supporting
Grpmax allele frequency cutoff of greater than 0.00163 in gnomAD.
Default Point Value:
-1
Modification Type:
Disease-specific
Not Applicable
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| BS2 | ||||
|
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.
Stand Alone
Very Strong
Strong
Default Point Value:
-4
Moderate
Default Point Value:
-2
Supporting
Default Point Value:
-1
Not Applicable
Comments:
This code is not applicable as the age of onset is variable and penetrance is known to be incomplete for some variants.
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| BS3 | ||||
|
Original ACMG Summary
Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.
VCEP Specifications:
Transgenic mouse models or conflicting minigene assay results should not be used as benign evidence. Stand Alone
Very Strong
Strong
Default Point Value:
-4
Moderate
Default Point Value:
-2
Supporting
See list of approved functional assays in PS3/BS3 Guidance spreadsheet below.
Default Point Value:
-1
Modification Type:
Disease-specific
Not Applicable
Comments:
This code is not applicable because there are no known functional assays that can dependably rule out pathogenicity.
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| BS4 | ||||
|
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
This code is applicable when there are two affected family members without the variant of interest.
Default Point Value:
-4
Modification Type:
Disease-specific
Moderate
Default Point Value:
-2
Supporting
Default Point Value:
-1
Not Applicable
Comments:
This code is not applicable as some variants are mild and may not produce a phenotype if inherited in trans with another mild ABCA4 variant.
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| BP1 | ||||
|
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
Comments:
Rule code does not apply as truncating variants do not predominate and missense variants are a known cause of disease.
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| BP2 | ||||
|
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
Default Point Value:
-1
Not Applicable
Comments:
Rule code does not apply because some modifier gene variants are in cis with known pathogenic variants.
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| BP3 | ||||
|
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
Comments:
There are no known repetitive regions without known function.
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| BP4 | ||||
|
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
This code is applicable for missense variants with a REVEL score of <0.184 or for synonymous or indel variants with a CADD score of less than or equal to 17.3 (PMID: 40225145).
Default Point Value:
-2
Modification Type:
Gene-specific
Supporting
This code is applicable for missense variants with a REVEL score between 0.184-0.290 or for synonymous or indel variants with a CADD score between 17.4-20 (PMID: 40225145). This code is also applicable for intronic variants where BP7 is not applicable and the SpliceAI score is < or = 0.1.
Default Point Value:
-1
Modification Type:
Gene-specific
Not Applicable
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| BP5 | ||||
|
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
Comments:
Do not use this rule as an individual can be a carrier of a pathogenic ABCA4 variant while having another molecular etiology for their retinopathy.
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| 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
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| BP7 | ||||
|
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.
VCEP Specifications:
BP4 is not used in combination with this rule code. Stand Alone
Very Strong
Strong
Default Point Value:
-4
Moderate
Rule code is applicable to intronic (outside of canonical -21 to +7) or synonymous variant when Splice AI prediction is <0.1 (PMID: 40225145). This code does not apply when conflicting minigene or other functional data is available.
Default Point Value:
-2
Modification Type:
Gene-specific
Supporting
Default Point Value:
-1
Not Applicable
|
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| Category | Point Ranges |
|---|---|
| Pathogenic | 10 |
| Likely Pathogenic | 6 - 9 |
| Uncertain Significance | 0 - 5 |
| Likely Benign | -6 - -1 |
| Benign | -7 |
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Questions or comments?
