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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Modification to the combining criteria such that one Benign Strong reaches Likely Benign (in the absence of conflicting evidence).
Criteria & Strength Specifications
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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. Stand Alone
Very Strong
Null variant in a gene where loss of function is a known mechanism of disease.
Modification Type:
Disease-specific
Strong
Moderate
Null variant in a gene where loss of function is a known mechanism of disease.
Modification Type:
Disease-specific
Supporting
Instructions:
Initiation codon variants are not applicable due to the MECP2E1 alternative isoform that excludes exon 1 with an alterante start codon. For intragenic deletions/duplications that are predicted to result in a product that preserves reading frame:
Not Applicable
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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
Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
Modification Type:
None
Moderate
Supporting
Not Applicable
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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. Stand Alone
Very Strong
De novo (maternity and paternity confirmed) in a patient with the disease and no family history.
Modification Type:
None
Strong
De novo (maternity and paternity confirmed) in a patient with the disease and no family history.
Modification Type:
None
Moderate
Supporting
Instructions:
Applicable to all genes in affected individuals identified as mosaic for the variant (as the presence of a variant in the mosaic state is confirmatory of the variant being de novo). Because of the very high de novo rate of pathogenic variants in MECP2, de novo observation can be attributed the highest value points per proband (2 points for confirmed de novo and 1 point for assumed de novo) if the patient is known to be affected with a neurodevelopmental phenotype consistent with the gene. Not Applicable
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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
Well-established in vitro or in vivo functional studies supportive of a damaging effect.
Modification Type:
Disease-specific
Moderate
Supporting
Well-established in vitro or in vivo functional studies supportive of a damaging effect.
Modification Type:
Disease-specific
Not Applicable
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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. Stand Alone
Very Strong
Strong
The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.
Modification Type:
Strength
Moderate
The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.
Modification Type:
Strength
Supporting
The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.
Modification Type:
Strength
Instructions:
Not Applicable
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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
Located in a mutational hot spot and/or critical and well-established functional domain.
Modification Type:
Disease-specific
Supporting
Not Applicable
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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
Absent/rare from controls in an ethnically-matched cohort population sample.
Modification Type:
Strength
Not Applicable
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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. Stand Alone
Very Strong
Strong
Moderate
Supporting
Not Applicable
Comments:
Not applicable for MECP2.
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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
Protein length changes due to stop-loss variants.
Modification Type:
Disease-specific
Moderate
Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.
Modification Type:
Disease-specific
Supporting
Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.
Modification Type:
Strength
Not Applicable
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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. Stand Alone
Very Strong
Strong
Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
Modification Type:
Strength
Moderate
Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
Modification Type:
None
Supporting
Not Applicable
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PM6 | ||||
Original ACMG Summary
Assumed de novo, but without confirmation of paternity and maternity.
Stand Alone
Very Strong
Confirmed de novo without confirmation of paternity and maternity.
Modification Type:
Strength
Strong
Confirmed de novo without confirmation of paternity and maternity.
Modification Type:
Strength
Moderate
Confirmed de novo without confirmation of paternity and maternity.
Modification Type:
None
Supporting
Instructions:
Because of the very high de novo rate of pathogenic variants in MECP2, de novo observation can be attributed the highest value points per proband (2 points for confirmed de novo and 1 point for assumed de novo) if the patient is known to be affected with a neurodevelopmental phenotype consistent with the gene. Not Applicable
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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. Stand Alone
Very Strong
Strong
Co-segregation with disease in multiple affected family members.
Modification Type:
Strength
Moderate
Co-segregation with disease in multiple affected family members.
Modification Type:
Strength
Supporting
Co-segregation with disease in multiple affected family members.
Modification Type:
Strength
Instructions:
Note: Individuals must have disease consistent with reported phenotype (even if on the mild end of spectrum of the disease). 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
Not Applicable
Comments:
Not applicable for MECP2.
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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:
None
Not Applicable
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PP4 | ||||
Original ACMG Summary
Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.
Stand Alone
Very Strong
Strong
Moderate
Supporting
Phenotype specific for disease with single genetic etiology.
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
Modification Type:
Disease-specific
Very Strong
Strong
Moderate
Supporting
Instructions:
The frequency cutoff is based on summation of prevalence of genes covered in the Rett/Angelman-like working group. The prevalence values were determined using the most conservative numbers found in the literature. Not Applicable
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BS1 | ||||
Original ACMG Summary
Allele frequency is greater than expected for disorder.
Stand Alone
Very Strong
Strong
Modification Type:
Disease-specific
Moderate
Supporting
Instructions:
The frequency cutoffs are based on MECP2 expected disease allele frequency (1 in 8500 females/1.5 alleles [assumes 50/50 male/female ratio]). MECP2 is the most prevalent of the genes covered in the Rett/Angelman-like working group and was chosen as most conservative number. 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
Observed in the heterozygous/hemizygous state in a healthy adult.
Modification Type:
Strength
Moderate
Supporting
Observed in the heterozygous/hemizygous state in a healthy adult.
Modification Type:
Strength
Instructions:
Not Applicable
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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.
Stand Alone
Very Strong
Strong
Well-established in vitro or in vivo functional studies shows no damaging effect on protein function.
Modification Type:
Disease-specific
Moderate
Supporting
Not Applicable
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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
Lack of segregation in affected members of a family.
Modification Type:
Strength
Moderate
Supporting
Lack of segregation in affected members of a family.
Modification Type:
Strength
Instructions:
Need to confirm that the family member is ‘affected with a neurodevelopmental phenotype consistent with the gene’ at a minimum. Not Applicable
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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
Moderate
Supporting
Not Applicable
Comments:
Not applicable for MECP2.
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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
Moderate
Supporting
Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder.
Modification Type:
Disease-specific
Instructions:
Knock out of MECP2 results in embryonic lethality/drastic phenotype.1 Not Applicable
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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
Moderate
Supporting
Not Applicable
Comments:
Not applicable for MECP2.
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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
Moderate
Supporting
Modification Type:
None
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
Variant found in a case with an alternate molecular basis for disease.
Modification Type:
Strength
Moderate
Supporting
Variant found in a case with an alternate molecular basis for disease.
Modification Type:
Disease-specific
Instructions:
Not Applicable
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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.
Stand Alone
Very Strong
Strong
Moderate
Supporting
A synonymous (silent) 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.
Modification Type:
None
Instructions:
For silent variants BP4 and BP7 can be added. Not Applicable
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