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.
For general information about the ClinGen Expert Panels and Variant Curation please visit: Clinical Domain Working Groups. For specific inquiries regarding content correction or adding a new criteria specification refer to the Help page.
Should you encounter any issues regarding the data displayed, lack of functionality or other problems, please let us know by contacting us via email.
Updated:
PM5_Strong
PM5_Moderate
PM5_Supporting
PM5 Instructions
PP4 - attachment table updates
PP4 instructions - edited and made sure was harrmonious with attached PP4 Tables
PM3 - attachment criterion table updates
Added ≥2 Supporting to Likely Benign Rules for Combining Criteria
| Criteria & Strength Specifications
|
||||
|---|---|---|---|---|
| PVS1 | ||||
|
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:
See attached PVS1 flowchart. Stand Alone
Very Strong
Use ClinGen SVI recommendations for loss of function criterion (Tayoun et al., 2018 (PMID: 30192042)).
Modification Type:
General recommendation,Gene-specific
Strong
Use ClinGen SVI recommendations for loss of function criterion (Tayoun et al., 2018 (PMID: 30192042)) with two specifications:
Modification Type:
General recommendation,Gene-specific
Moderate
Use ClinGen SVI recommendations for loss of function criterion (Tayoun et al., 2018 (PMID: 30192042)) with one specification:
Modification Type:
General recommendation
Supporting
Not Applicable
|
||||
| PS1 | ||||
|
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
It can also be applied for splice variants at the same nucleotide and with similar impact prediction as previously reported pathogenic variant (if the predicted impact is equal to or greater than the known pathogenic variant per in silico splicing tool SpliceAI). - Example: c.105+1G>C is known to be pathogenic, can use PS1 for c.105+1G>T. Applicable if the previously established variant is classified as pathogenic by SCID VCEP specifications for IL7R.
Modification Type:
Gene-specific
Moderate
It can also be applied for splice variants at the same nucleotide and with similar impact prediction as previously reported pathogenic variant (if the predicted impact is equal to or greater than the known pathogenic variant per in silico splicing tool SpliceAI). - Example: c.105+1G>C is known to be likely pathogenic, can use PS1 for c.105+1G>T Applicable if the previously established variant is classified as likely pathogenic by SCID VCEP specifications for IL7R.
Modification Type:
Gene-specific,Strength
Supporting
Not Applicable
|
||||
| PS2 | ||||
|
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:
The following guidelines should be used when determining the phenotypic consistency of each proband:
Stand Alone
Very Strong
Use ClinGen SVI recommendations for de novo criteria (see instructions below).
Modification Type:
General recommendation,Gene-specific
Strong
Use ClinGen SVI recommendations for de novo criteria (see instructions below).
Modification Type:
General recommendation,Gene-specific
Moderate
Use ClinGen SVI recommendations for de novo criteria (see instructions below).
Modification Type:
General recommendation,Gene-specific
Supporting
Use ClinGen SVI recommendations for de novo criteria (see instructions below).
Modification Type:
General recommendation,Gene-specific
Not Applicable
|
||||
| PS3 | ||||
|
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
Strong
PS3 may potentially be applied at the default strength level of strong for evidence from an animal model expressing the variant of interest and recapitulating the IL7R-SCID phenotype. Animal models will be reviewed on a case-by-case basis by the VCEP to determine the appropriate strength level.
Modification Type:
Gene-specific
Moderate
Supporting
PS3_Supporting can be applied based on an abnormal result in at least one approved in vitro assay (IL-7-induced Jak3 phosphorylation assay, IL-7 binding assay, IL-7-induced STAT5 DNA binding/transcriptional induction).
At least one previously observed proband with the expressed IL7R variant meeting PP4 is required to apply PS3 at any strength on the basis of a cellular model/in vitro study.
Modification Type:
Gene-specific,Strength
Not Applicable
|
||||
| PS4 | ||||
|
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:
When the variant has been detected in multiple unrelated affected individuals (with at least one core feature of T lymphopenia, congenital alopecia, and nail dystrophy), evaluate each proband with the PP4 criteria (see below) and add points across all probands. Exclude the proband used to satisfy the PP4 criteria and cap each additional proband’s contribution at 2pt.
Stand Alone
Very Strong
Strong
Moderate
Supporting
Not Applicable
|
||||
| PM1 | ||||
|
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
Moderate
Supporting
Not Applicable
|
||||
| PM2 | ||||
|
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
Supporting
gnomAD popmax filtering allele frequency <0.00004129.
Modification Type:
Gene-specific
Not Applicable
|
||||
| PM3 | ||||
|
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:
Use ClinGen SVI adapted recommendations for in trans criterion (https://clinicalgenome.org/site/assets/files/3717/svi_proposal_for_pm3_criterion_-_version_1.pdf) with the additional requirement that the co-occurring variant must be classified using the SCID VCEP specifications for IL7R. Caveat: All variants should be sufficiently rare (meet PM2 specification). The applicability of PM3 to suspected founder variants with allele frequencies exceeding the PM2 threshold will be evaluated on a case-by-case basis by the VCEP. Stand Alone
Very Strong
Use ClinGen SVI adapted recommendations for in trans criterion with the additional requirement that the co-occurring variant must be classified using the SCID VCEP specifications for IL7R.
Modification Type:
General recommendation,Strength
Strong
Use ClinGen SVI adapted recommendations for in trans criterion with the additional requirement that the co-occurring variant must be classified using the SCID VCEP specifications for IL7R.
Modification Type:
General recommendation,Strength
Moderate
Use ClinGen SVI adapted recommendations for in trans criterion with the additional requirement that the co-occurring variant must be classified using the SCID VCEP specifications for IL7R.
Modification Type:
General recommendation,Strength
Supporting
Use ClinGen SVI adapted recommendations for in trans criterion with the additional requirement that the co-occurring variant must be classified using the SCID VCEP specifications for IL7R.
Modification Type:
General recommendation,Strength
Not Applicable
|
||||
| PM4 | ||||
|
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
Moderate
When applied to deletion variants, the deleted region must contain a known pathogenic or likely pathogenic variant that is not predicted/observed to alter splicing.
Modification Type:
Gene-specific
Supporting
When applied to deletion variants, the deleted region must contain a known VUS variant that is not predicted/observed to alter splicing.
Modification Type:
Gene-specific,Strength
Not Applicable
|
||||
| PM5 | ||||
|
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:
For nonsense variants: PM5_Strong
PM5_Moderate
PM5_Supporting
Type of variant under assessment (VUA); Informative variant; Score Nonsense variant predicted to lead to NMD; P/LP variant in the exon of DNA change predicted to lead to NMD; +1pt Nonsense variant predicted to lead to NMD; B/LB variant in the exon predicted to lead to NMD; -2pt Nonsense variant, resulting in a PTC in the final exon, not predicted to lead to NMD; P/LP variant resulting in a PTC in the same exon but downstream of VUA; +1pt Nonsense variant, resulting in a PTC in the final exon, not predicted to lead to NMD; B/LB variant resulting in PTC in the same exon but upstream of the VUA; -2pt NMD = nonsense-mediated decay; PTC premature termination codon Note: The informative variant must be classified by the SCID VCEP specifications and may not be the same variant used to meet “+1 pathogenic variant downstream” on the PVS1 flowchart. If negative points are calculated, the curator should not apply PM5 and should reconsider if PVS1 is applicable for the VUA. The VUA must be sufficiently rare, meet PM2_Supporting, to apply this point system. If the informative variant is a frameshift or nonsense variant, it must reach classification as Pathogenic or Likely Pathogenic without use of PM5 and without use of only PVS1 plus PM2. Stand Alone
Very Strong
Strong
PM5 may be applied at a Strong level of evidence for any nonsense variant with 4+ points from informative variants (see below point table). PM5_Strong should be downgraded to PM5_Moderate if PVS1 is applied at any strength. Notes: The informative variant must be classified by the SCID VCEP specifications and may not be the same variant used to meet “+1 pathogenic variant downstream” on the PVS1 flowchart. If negative points are calculated, the curator should not apply PM5 and should reconsider if PVS1 is applicable for the VUA. The VUA must be sufficiently rare, meet PM2_Supporting, to apply this point system. If the informative variant is a frameshift or nonsense variant, it must reach classification as Pathogenic or Likely Pathogenic without use of PM5 and without use of only PVS1 plus PM2.
Modification Type:
General recommendation,Strength
Moderate
Applicable at default strength (PM5) if previously established variant is classified as pathogenic or at reduced strength of PM5_Supporting if previously established variant is classified as likely pathogenic. Notes: The informative variant must be classified by the SCID VCEP specifications and may not be the same variant used to meet “+1 pathogenic variant downstream” on the PVS1 flowchart. If negative points are calculated, the curator should not apply PM5 and should reconsider if PVS1 is applicable for the VUA. The VUA must be sufficiently rare, meet PM2_Supporting, to apply this point system. If the informative variant is a frameshift or nonsense variant, it must reach classification as Pathogenic or Likely Pathogenic without use of PM5 and without use of only PVS1 plus PM2.
Modification Type:
General recommendation,Strength
Supporting
Applicable at default strength (PM5) if previously established variant is classified as pathogenic or at reduced strength of PM5_Supporting if previously established variant is classified as likely pathogenic. Also applicable to a nonsense variant with 1 point from an informative variant (see point table). Informative variants must also be classified by these rule specifications. Notes: The informative variant must be classified by the SCID VCEP specifications and may not be the same variant used to meet “+1 pathogenic variant downstream” on the PVS1 flowchart. If negative points are calculated, the curator should not apply PM5 and should reconsider if PVS1 is applicable for the VUA. The VUA must be sufficiently rare, meet PM2_Supporting, to apply this point system. If the informative variant is a frameshift or nonsense variant, it must reach classification as Pathogenic or Likely Pathogenic without use of PM5 and without use of only PVS1 plus PM2.
Modification Type:
Gene-specific,Strength
Not Applicable
|
||||
| PM6 | ||||
|
Original ACMG Summary
Assumed de novo, but without confirmation of paternity and maternity.
VCEP Specifications:
The following guidelines should be used when determining the phenotypic consistency of each proband:
Stand Alone
Very Strong
Strong
Use ClinGen SVI recommendations for de novo criteria (see instructions below).
Modification Type:
General recommendation,Gene-specific
Moderate
Use ClinGen SVI recommendations for de novo criteria (see instructions below).
Modification Type:
General recommendation,Gene-specific
Supporting
Use ClinGen SVI recommendations for de novo criteria (see instructions below).
Modification Type:
General recommendation,Gene-specific
Not Applicable
|
||||
| PP1 | ||||
|
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:
Use ClinGen SVI recommendations for co-segregation criterion (PMID: 30311386) with the additional specification that unaffected individuals contributing to the calculated LOD score (Attached document: PP1 specifications) must be heterozygous carriers of one of the variants observed in the affected individuals (i.e. do not count wild-type/wild-type, individuals). Stand Alone
Very Strong
Strong
Use recommendations for co-segregation criterion from PMID: 30311386, with strength dependent on number of affected segregations.
Modification Type:
General recommendation
Moderate
Use recommendations for co-segregation criterion from PMID: 30311386, with strength dependent on number of affected segregations.
Modification Type:
General recommendation
Supporting
Use recommendations for co-segregation criterion from PMID: 30311386, with strength dependent on number of affected segregations.
Modification Type:
General recommendation
Not Applicable
|
||||
| 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
Not Applicable
Comments:
Does not apply. The gnomAD v2.1.1 missense Z score for IL7R (Z = -1.29) suggests this gene is not constrained for missense variation. Both benign and pathogenic missense variants are present in IL7R.
|
||||
| PP3 | ||||
|
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
Moderate
Supporting
Modification Type:
General recommendation
Not Applicable
|
||||
| PP4 | ||||
|
Original ACMG Summary
Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.
VCEP Specifications:
PP4 applicability and strength is determined by the total points accumulated by a single affected individual according to the table below and the following total point ranges:
Evidence Description (Points) Diagnostic criteria met for SCID (Criteria 1 and 3 or Criterion 4 by itself) or Leaky SCID/Omenn syndrome (excluding Criterion 2)2 (0.5pt) SCID gene panel or exome/genome sequencing conducted (only applicable if genetic testing did not provide an alternative genetic explanation for SCID/Leaky SCID/Omenn syndrome phenotype) (1pt) Family history of SCID (only applicable if SCID gene panel or exome/genome sequencing was conducted on proband and did not provide an alternative genetic explanation for phenotype) (0.5pt) Absent CD127 expression (demonstrated by RT-PCR, Western blot, flow cytometry) PMIDs: 9843216, 11023514, 17827065 (4.5 pt) Reduced CD127 expression (demonstrated by RT-PCR, or Western blot) as established by the laboratory PMIDs: 9843216, 11023514, 17827065 (3 pt) Reduced CD127 expression (demonstrated by flow cytometry) as established by the laboratory AND pathogenic or likely pathogenic variants in IL2RG have been excluded; OR reduced IL-7-induced phosphorylation of STAT5 in patient-derived T-cells as established by the laboratory AND pathogenic or likely pathogenic variants in IL2RG, JAK3, STAT5A, and STAT5B have been excluded PMID: 38587703 (3 pt) Reduced CD127 expression (demonstrated by flow cytometry) as established by the laboratory AND pathogenic or likely pathogenic variants in IL2RG have been excluded; OR reduced IL-7-induced phosphorylation of STAT5 in patient-derived T-cells as established by the laboratory AND pathogenic or likely pathogenic variants in IL2RG, JAK3, STAT5A, and STAT5B have NOT been excluded PMID: 38587703 (1 pt) SCID phenotype corrected by IL7R gene therapy WITHOUT CNV testing performed (4.5 pt) SCID phenotype corrected by IL7R gene therapy WITH CNV testing performed (6 pt) T-B+NK+ lymphocyte subset profile* (See notes) (0.25 pt) 1CNV (Copy number variation) testing is required to consider PP4_Strong in order to certify that the variant in question is the causative for the phenotype, and not one CNV event corrected by gene therapy and not identified previously. 2 The diagnostic criteria should follow the PIDTC 2022 specification, summarized here. *Notes: 1) If NK cells are not noted or are present, criteria may still be applied if SCID gene panel or exome/genome sequencing has ruled out alternative causes; 2) If maternal T cells are present, the T lymphocyte profile is still considered to be T- (autologous T cells are absent). Find attached the PP4 table. Stand Alone
Very Strong
Strong
A patient score of ≥ 6 points1. 1CNV (Copy number variation) testing is required to consider PP4_Strong in order to certify that the variant in question is the causative for the phenotype and not one CNV event corrected by gene therapy and not identified previously (see instructions below).
Modification Type:
Disease-specific,Gene-specific
Moderate
A patient score of 2-<6 points (see instructions below).
Modification Type:
Disease-specific,Gene-specific
Supporting
A patient score of 1-<2 points (see instructions below).
Modification Type:
Disease-specific,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 | ||||
|
Original ACMG Summary
Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
VCEP Specifications:
Maximum credible population allele frequency threshold is determined using Whiffin/Ware calculator (https://www.cardiodb.org/allelefrequencyapp/) and the following parameters:
Stand Alone
gnomAD popmax filtering allele frequency >0.00566.
Modification Type:
Gene-specific
Very Strong
Strong
Moderate
Supporting
Not Applicable
|
||||
| BS1 | ||||
|
Original ACMG Summary
Allele frequency is greater than expected for disorder.
VCEP Specifications:
gnomAD popmax filtering allele frequency >0.001261 Maximum credible population allele frequency threshold determined using Whiffin/Ware calculator (https://www.cardiodb.org/allelefrequencyapp/) and the following parameters:
1Consider also bottleneck populations. Stand Alone
Very Strong
Strong
gnomAD popmax filtering allele frequency >0.001261 1Consider also bottleneck populations.
Modification Type:
Gene-specific
Moderate
Supporting
Not Applicable
|
||||
| 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
Moderate
Supporting
Only to be used when the variant is observed in the homozygous state in a healthy adult.
Modification Type:
Strength
Not Applicable
Comments:
Does not apply due to reduced penetrance.
|
||||
| BS3 | ||||
|
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
Moderate
Supporting
Not Applicable
Comments:
There is not a well-established functional study which can rule out all damaging effects on protein function.
|
||||
| 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
Can be applied without additional specifications.
Modification Type:
None
Moderate
Supporting
Not Applicable
|
||||
| BP1 | ||||
|
Original ACMG Summary
Missense variant in a gene for which primarily truncating variants are known to cause disease.
Stand Alone
Very Strong
Strong
Moderate
Supporting
Not Applicable
Comments:
Does not apply. IL7R missense variants are a known mechanism of disease.
|
||||
| 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
Moderate
Supporting
Not Applicable
|
||||
| BP3 | ||||
|
Original ACMG Summary
In frame-deletions/insertions in a repetitive region without a known function.
Stand Alone
Very Strong
Strong
Moderate
Supporting
Not Applicable
Comments:
Does not apply.
|
||||
| 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
Moderate
Supporting
Not Applicable
|
||||
| BP5 | ||||
|
Original ACMG Summary
Variant found in a case with an alternate molecular basis for disease.
Stand Alone
Very Strong
Strong
Moderate
Supporting
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 | ||||
|
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
Moderate
Supporting
Modification Type:
Disease-specific
Not Applicable
|
||||
One Baylor Plaza, MS:BCM225 Suite 400D, Houston, TX, 77030
Questions or comments?
