Criteria Specification Registry

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 Specification

ClinGen Severe Combined Immunodeficiency Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RMRP Version 1.0.0

Description : RMRP specifications

Version : 1.0.0

Severe Combined Immunodeficiency Disease VCEP

Released

5/14/2025

19:02:26

Rules for RMRP

Gene: RMRP (HGNC:10031) HGNC Name: RNA component of mitochondrial RNA processing endoribonuclease Transcripts: NR_003051.3 Disease: cartilage-hair hypoplasia (MONDO:0009595) Mode of Inheritance: Autosomal recessive 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. Stand Alone Very Strong Strong Moderate Supporting Not Applicable Comments: Does not apply.
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. Stand Alone Very Strong Strong Moderate Supporting Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. Downgraded to PS1_Supporting. Applicable if a different nucleotide change at the same nucleotide position has been previously classified as pathogenic or likely pathogenic. Cannot be applied if a different nucleotide change at the same position has been previously classified as benign or likely benign. Previously established variants must be classified by SCID VCEP specifications for RMRP. Modification Type: Gene-specific,Strength 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: The following guidelines should be used when determining the phenotypic consistency of each proband: “Phenotype highly specific for gene” proband must meet PP4_Moderate criteria; “Phenotype consistent with gene but not highly specific” proband must meet PP4 criteria; “Phenotype consistent with gene but not highly specific and high genetic heterogeneity”: proband has been asserted to have a Cartilage-hair hypoplasia (CHH) phenotype but does not meet PP4 criteria; Reduce points per proband by half if the phase is unconfirmed. Stand Alone Very Strong Use ClinGen SVI recommendations for de novo criteria (see instructions below). Modification Type: Disease-specific,Strength Strong Use ClinGen SVI recommendations for de novo criteria (see instructions below). Modification Type: Disease-specific,Strength Moderate Use ClinGen SVI recommendations for de novo criteria (see instructions below). Modification Type: Disease-specific,Strength Supporting Use ClinGen SVI recommendations for de novo criteria (see instructions below). Modification Type: Disease-specific,Strength 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: PS3 may be applied when RT/PCR or RNA evidence indicates variant results in absent expression. 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 Cartilage-hair hypoplasia (CHH) 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. Approved assay instances: Endonucleolytic cleavage activity assay (mRNA cleavage activity smaller than 0.9) Thiel et al., 2005 (PMID: 16252239) Thiel et al., 2007 (PMID: 17701897)) OR Luciferase reporter assay Hermanns et al., 2005 (PMID: 16254002)) (luciferase activity higher than 7) At least one previously observed proband with the expressed RMRP variant meeting PP4 is required to apply PS3 at any strength. Modification Type: Disease-specific,Strength 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. Stand Alone Very Strong Strong Moderate Supporting Not Applicable Comments: Does not apply.
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 Defined to include insertions/duplications between the TATA box (spanning n.-32 to n.-24) and the transcription start site (n.4). Caveat: variant must also meet PM2. Modification Type: Gene-specific Moderate Supporting 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 Supporting Absent in population databases (or at extremely low frequency if recessive). Downgraded to PM2_Supporting. gnomAD popmax filtering allele frequency <0.0000447 The applicability of PM2 to suspected founder variants with allele frequencies exceeding the PM2 threshold will be evaluated on a case-by-case basis by the VCEP. Modification Type: Disease-specific,Strength 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. VCEP Specifications: Caveat: All variants should be sufficiently rare - variant does not have to meet PM2 specification criteria but variant should not meet BS1/BA1 criteria (unless a suspected founder variant). The applicability of PM3 to suspected founder variants exceeding the BS1/BA1 threshold will be evaluated on a case-by-case basis by the VCEP. Stand Alone Very Strong Use ClinGen SVI recommendations for in trans criterion with the additional requirement that the co-occurring variant must be classified using the SCID VCEP specifications for RMRP. Modification Type: General recommendation,Strength Strong Use ClinGen SVI recommendations for in trans criterion with the additional requirement that the co-occurring variant must be classified using the SCID VCEP specifications for RMRP. Modification Type: General recommendation,Strength Moderate Use ClinGen SVI recommendations for in trans criterion with the additional requirement that the co-occurring variant must be classified using the SCID VCEP specifications for RMRP. Modification Type: General recommendation Supporting Use ClinGen SVI recommendations for in trans criterion with the additional requirement that the co-occurring variant must be classified using the SCID VCEP specifications for RMRP. Modification Type: General recommendation,Strength Not Applicable
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. Stand Alone Very Strong Strong Moderate Defined to include insertions/duplications of 6 or more nucleotides increasing the distance between the TATA box (spanning n.-32 to n.-24) and the transcription start site (n.4). Modification Type: Gene-specific Supporting 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. Stand Alone Very Strong Strong Moderate Supporting Not Applicable Comments: Does not apply.
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: The following guidelines should be used when determining the phenotypic consistency of each proband: “Phenotype highly specific for gene” proband must meet PP4_Moderate criteria; “Phenotype consistent with gene but not highly specific” proband must meet PP4 criteria; “Phenotype consistent with gene but not highly specific and high genetic heterogeneity”: proband has been asserted to have a Cartilage-hair hypoplasia (CHH) phenotype but does not meet PP4 criteria; Reduce points per proband by half if the phase is unconfirmed. Stand Alone Very Strong Strong Use ClinGen SVI recommendations for de novo criteria (see instructions below). Modification Type: Disease-specific,Strength Moderate Use ClinGen SVI recommendations for de novo criteria (see instructions below). Modification Type: Disease-specific,Strength Supporting Use ClinGen SVI recommendations for de novo criteria (see instructions below). Modification Type: Disease-specific,Strength Not Applicable
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: 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,Strength Moderate Use recommendations for co-segregation criterion from PMID: 30311386, with strength dependent on number of affected segregations. Modification Type: General recommendation,Strength Supporting Use recommendations for co-segregation criterion from PMID: 30311386, with strength dependent on number of affected segregations. Modification Type: General recommendation,Strength 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. Stand Alone Very Strong Strong Moderate Supporting Not Applicable Comments: Does not apply.
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 Moderate Supporting Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc). Use RNAsnp to access SNP effects on local RNA secondary structure (https://rth.dk/resources/rnasnp/) Use only for Single Nucleotide Polymorphism inside the gene (do not use for promoter sequence) Parameters utilized: Input sequence: FASTA (Ensembl NR__003051.3) Insert SNP details Mode: 1 Folding window: 100 nt Measure: “Distance” option Minimum length of the sequence interval: 50 Cut-off the base pair probabilities: 0.01 The p-value threshold significance should be considered 0.1 according to Sabarinathan et al., 2013. PMID: 23315997. If the value is less than 0.1, apply PP3 as a supporting level of evidence. Modification Type: Gene-specific,Strength 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: PP4 applicability and strength is determined by the total points accumulated by a single affected individual according to the list below and the following total point ranges: <1 point: PP4 not met 1-<2 points: PP4 ≥2 points: PP4_Moderate Diagnostic criteria for SCID/Leaky SCID/Omenn syndrome met¹ 1pt 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) 0.5pt Family history of SCID 0.5pt Family history of CHH 1pt Metaphyseal dysplasia (disproportionate short stature + radiographic evidence) 1pt Skeletal dysplasia gene panel or WES/WGS conducted with no alternative genetic diagnosis 1pt Hypotrichosis 0.5 pt Macrocytic, hypoplastic anemia 0.25pt Hirschsprung disease or congenital megacolon 0.25pt T-cell lymphopenia* (see notes) 0.5 pt ¹The diagnostic criteria should follow the PIDTC 2022 specification, summarized here. *Notes: If maternal T cells are present, the T lymphocyte profile is still considered to be T- (autologous T cells are absent). Allocate 0.25 points for T-cell lymphopenia only in cases where the SCID diagnostic criteria are not applied. It is important to note that if the SCID diagnostic criteria were applied, the points for the T-B+NK+ lymphocyte subset profile cannot be considered. Stand Alone Very Strong Strong Moderate A patient score of ≥2 points (see instructions below). Modification Type: Disease-specific,Gene-specific,Strength 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 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 Common in population databases. gnomAD popmax filtering allele frequency >0.00400 Maximum credible population allele frequency threshold determined using Whiffin/Ware calculator (https://www.cardiodb.org/allelefrequencyapp/) and the following parameters: Prevalence: 1:5,000 Allelic heterogeneity: 1 Genetic heterogeneity: 0.04 (based on the contribution of RMRP variants to total SCID in the PIDTC 6901 cohort reported in Dvorak et al., 2019 (PMID: 30193840, Table 1): 3.6%, rounded to 4%) Penetrance: 50% Use caution when applying BA1 based on allele frequencies derived from gnomAD exome sequencing given the reduced coverage of certain regions of RMRP. Ensure at least 20X read depth for allele frequencies derived from exome sequencing. Modification Type: Disease-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 Allele frequency is greater than expected for disorder. gnomAD popmax filtering allele frequency >0.00089 Maximum credible population allele frequency threshold determined using Whiffin/Ware calculator (https://www.cardiodb.org/allelefrequencyapp/) and the following parameters: Prevalence: 1:50,000 Allelic heterogeneity: 1 Genetic heterogeneity: 0.04 (based on the contribution of RMRP variants to total SCID in the PIDTC 6901 cohort reported in Dvorak et al., 2019 (PMID: 30193840, Table 1): 3.6%, rounded to 4%) Penetrance: 100% Use caution when applying BS1 based on allele frequencies derived from gnomAD exome sequencing given the reduced coverage of certain regions of RMRP. Ensure at least 20X read depth for allele frequencies derived from exome sequencing. Modification Type: Disease-specific Moderate Supporting 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. Stand Alone Very Strong Strong BS2_Strong: Observed in >=3 (3 or more) homozygotes in gnomAD. Modification Type: Gene-specific,Strength Moderate Supporting BS2_Supporting: Can be applied at Supporting level of evidence if observed at least 2 homozygotes in gnomAD. Modification Type: Gene-specific,Strength 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 Moderate Supporting Not Applicable Comments: Does not apply.
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 Can be applied without additional specifications. To apply the BS4 criteria, it is sufficient to have one affected family member without the segregation of the variant. Modification Type: None Moderate Supporting 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 Moderate Supporting Not Applicable Comments: Does not apply.
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 Moderate Supporting Not Applicable Comments: Does not apply.
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 Moderate Supporting Not Applicable Comments: Does not apply.
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 Moderate Supporting Not Applicable Comments: Does not apply.
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 Moderate Supporting Not Applicable Comments: Does not apply.
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 Moderate Supporting Not Applicable Comments: Does not apply.

Rules for Combining Criteria

Pathogenic

1 Very Strong (PS2_Very Strong, PM3_Very Strong) AND ≥ 1 Strong (PS2, PS3, PM3_Strong, PM6_Strong, PP1_Strong)

1 Very Strong (PS2_Very Strong, PM3_Very Strong) AND ≥ 2 Moderate (PS2_Moderate, PM1, PM3, PM6, PP1_Moderate)

1 Very Strong (PS2_Very Strong, PM3_Very Strong) AND 1 Moderate (PS2_Moderate, PM1, PM3, PM6, PP1_Moderate) AND 1 Supporting (PS1_Supporting, PS2_Supporting, PM2_Supporting, PM3_Supporting, PM6_Supporting, PP1, PP3, PP4)

1 Very Strong (PS2_Very Strong, PM3_Very Strong) AND ≥ 2 Supporting (PS1_Supporting, PS2_Supporting, PM2_Supporting, PM3_Supporting, PM6_Supporting, PP1, PP3, PP4)

≥ 2 Strong (PS2, PS3, PM3_Strong, PM6_Strong, PP1_Strong)

1 Strong (PS2, PS3, PM3_Strong, PM6_Strong, PP1_Strong) AND ≥ 3 Moderate (PS2_Moderate, PM1, PM3, PM6, PP1_Moderate)

1 Strong (PS2, PS3, PM3_Strong, PM6_Strong, PP1_Strong) AND 2 Moderate (PS2_Moderate, PM1, PM3, PM6, PP1_Moderate) AND ≥ 2 Supporting (PS1_Supporting, PS2_Supporting, PM2_Supporting, PM3_Supporting, PM6_Supporting, PP1, PP3, PP4)

1 Strong (PS2, PS3, PM3_Strong, PM6_Strong, PP1_Strong) AND 1 Moderate (PS2_Moderate, PM1, PM3, PM6, PP1_Moderate) AND ≥ 4 Supporting (PS1_Supporting, PS2_Supporting, PM2_Supporting, PM3_Supporting, PM6_Supporting, PP1, PP3, PP4)

Likely Pathogenic

1 Very Strong (PS2_Very Strong, PM3_Very Strong) AND 1 Moderate (PS2_Moderate, PM1, PM3, PM6, PP1_Moderate)

1 Very Strong (PS2_Very Strong, PM3_Very Strong) AND 1 Supporting (PS1_Supporting, PS2_Supporting, PS3_Supporting, PM2_Supporting, PM3_Supporting, PM6_Supporting, PP1, PP3, PP4)

1 Strong (PS2, PS3, PM3_Strong, PM6_Strong, PP1_Strong) AND 1 Moderate (PS2_Moderate, PS3_Moderate, PM1, PM3, PM6, PP1_Moderate, PP4_Moderate)

1 Strong (PS2, PS3, PM3_Strong, PM6_Strong, PP1_Strong) AND ≥ 2 Supporting (PS1_Supporting, PS2_Supporting, PS3_Supporting, PM2_Supporting, PM3_Supporting, PM6_Supporting, PP1, PP3, PP4)

≥ 3 Moderate (PS2_Moderate, PS3_Moderate, PM1, PM3, PM6, PP1_Moderate, PP4_Moderate)

2 Moderate (PS2_Moderate, PS3_Moderate, PM1, PM3, PM6, PP1_Moderate, PP4_Moderate) AND ≥ 2 Supporting (PS1_Supporting, PS2_Supporting, PS3_Supporting, PM2_Supporting, PM3_Supporting, PM6_Supporting, PP1, PP3, PP4)

1 Moderate (PS2_Moderate, PS3_Moderate, PM1, PM3, PM6, PP1_Moderate, PP4_Moderate) AND ≥ 4 Supporting (PS1_Supporting, PS2_Supporting, PS3_Supporting, PM2_Supporting, PM3_Supporting, PM6_Supporting, PP1, PP3, PP4)

Benign

≥ 2 Strong (BS1, BS4)

1 Stand Alone (BA1)

Likely Benign

1 Strong (BS1, BS2, BS4)

≥ 2 Supporting (BS2_Supporting)

Files & Images

PS2_PM6: SVI recommendations for de novo criteria

PM3: SVI recommendations for pm3 criterion

PS3_BS3: RMRP Functional Evidence

PP1: Specifications