Criteria Specification Registry

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Criteria Specification

ClinGen Congenital Myopathies Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RYR1 Version 1.0.0

Description : The Congenital Myopathies VCEP aims to (1) define criteria for the specific classification of variants related to congenital myopathies based on the ACMG standards and guidelines for variant interpretation and classification, and (2) review the majority of reported variants that have been associated with these disorders to provide expert-approved classification for their clinical significance, starting with 5 genes that have been described as having Definitive evidence for a causal role in disease: ACTA1, NEB, MTM1, DNM2, RYR1

Version : 1.0.0

Congenital Myopathies VCEP

Released

8/7/2024

14:13:49

Rules for RYR1

Note on multiple MOIs: In general, the easiest way to tell whether a variant is AD or AR is to look at the clinical situation of probands with the variant, along with the family and inheritance. If it’s de novo, it’s much more likely to be AD and if it’s observed with a second variant, it’s much more likely to be AR. In general, loss of function variants are almost always associated with AR disease. If two missense variants are identified in trans, individuals are much more likely to have central core or minicore disease. Malignant hyperthermia is only associated with AD variants. However, there have been some examples of a missense MH variant in trans with a LOF variant, causing a blended phenotype of myopathy and MH susceptibility. The AD and AR specifications are listed separately.

Gene: RYR1 (HGNC:10483) HGNC Name: ryanodine receptor 1 Transcripts: NM_000540.3 Disease: RYR1-related myopathy (MONDO:0100150) 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 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. Modification Type: Disease-specific,Gene-specific Strong In-frame deletions or in frame exon-skipping variants in the pore/transmembrane region of RYR1 should be scored at PVS1_strong. (Amino acids 4800-4950, Exons 100-103) Modification Type: Gene-specific Moderate See PVS1 flowchart Modification Type: Disease-specific,Gene-specific Supporting See PVS1 flowchart Modification Type: Disease-specific,Gene-specific Instructions: RYR1 is associated with both dominant and recessive myopathy. Loss of function is only a mechanism for autosomal recessive (AR) disease and PVS1 should only be applied for AR variants. Not Applicable
PS1 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. Example: Val->Leu caused by either G>C or G>T in the same codon. Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level. Stand Alone Very Strong Strong 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. Modification Type: No change Moderate No change - use as originally described Modification Type: No change Supporting No change - use as originally described Modification Type: No change 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. Stand Alone Very Strong No change - use as originally described Modification Type: No change Strong 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. Modification Type: No change Moderate No change - use as originally described Modification Type: No change Supporting No change - use as originally described Modification Type: No change 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. Stand Alone Very Strong Strong Strong may only be considered for variant-specific mouse models. Currently, no other assays are applicable at this strength. Modification Type: Disease-specific Moderate Supporting There are no specified functional assay for AR RYR1-related myopathy. However, it is acceptable to use PS3_Supporting for other functional analyses if The assay has been validated by a known pathogenic and benign variant AND There is plausible reason that the function the assay is testing relates to the phenotype AND The assay conditions are likely to mimic the physiological environment. Modification Type: Gene-specific Instructions: Specified assays are only provided for the AD specifications, which are listed separately. 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 Instructions: RYR1 is associated with both autosomal recessive and autosomal dominant disease; both PS4 and PM3 can be used for proband counting. Please use PM3 for biallelic case observations. Please see PS4 chart. PS4 cannot be combined with PP4. Not Applicable Comments: These specifications are only for autosomal recessively inherited RYR1 variants. Please use PM3 for case counting. There are separate specifications for AD RYR1 variants.
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 Moderate The pore/transmembrane region of RYR1 is critical for protein function and missense variants that fall within this region (amino acids 4800-4950) Modification Type: Disease-specific,Gene-specific Supporting Not Applicable Comments: There are no defined hotspots or critical functional domains in ACTA1 at this time.
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 PM2_Supporting may be applied if the minor allele frequency in population databases of at least 2000 alleles is ≤ 0.00000697 for autosomal recessive Modification Type: Disease-specific,Gene-specific Instructions: If the mode of inheritance for the variant is unclear (largely with missense variants as loss of function variants are predicted to cause AR disease), use the more conservative AD cutoff and specifications for PM2_Supporting. Not Applicable
PM3 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary For recessive disorders, detected in trans with a pathogenic variant Note: This requires testing of parents (or offspring) to determine phase. Stand Alone Very Strong 4.0 points per the PM3 chart Modification Type: Disease-specific,Gene-specific Strong 2.0 points per the PM3 chart Modification Type: Disease-specific,Gene-specific Moderate For recessive disorders, detected in trans with a pathogenic variant Note: This requires testing of parents (or offspring) to determine phase. 1.0 points per the PM3 chart Modification Type: Disease-specific,Gene-specific Supporting 0.5 points per the PM3 chart Modification Type: Disease-specific,Gene-specific Instructions: Please use this SVI-recommended PM3 chart to count observations. Points for each proband should be summed to get to a final PM3 strength. In order to count to count case counts for your variant of interest, it should be rare enough to not meet BS1. For variants that follow an autosomal dominant mode of inheritance, please use the separate AD specifications. PM3 Chart 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 No change - use as originally described Modification Type: No change Moderate Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants. Modification Type: No change Supporting No change - use as originally described Modification Type: No change Instructions: Either PVS1_Strong or PM4_Strong, but not both, should be used for in-frame deletions in the pore region (Amino acids 4800-4950) of RYR1. 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 No change - use as originally described Modification Type: No change Moderate 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. Modification Type: No change Supporting No change - use as originally described Modification Type: No change Not Applicable
PM6 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Assumed de novo, but without confirmation of paternity and maternity. Stand Alone Very Strong Strong No change - use as originally described Modification Type: No change Moderate Assumed de novo, but without confirmation of paternity and maternity. Modification Type: No change Supporting No change - use as originally described Modification Type: No change 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. Stand Alone Very Strong Strong See segregation chart Modification Type: General recommendation Moderate See segregation chart Modification Type: General recommendation Supporting 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. See segregation chart Modification Type: General recommendation Instructions: The segregation chart (adopted from Oza et al 2018 PMID:30311386) should be used to determine the strength level of the total number of affected and unaffected segregations. In order to count unaffected segregations, the unaffected individuals can be heterozygous carriers or WT, but should have the same risk of inheriting the variant as the affected individuals (e.g. siblings in the same generation). Segregation chart 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: RYR1 is not a gene that is constrained for missense variation. Hence PP2 is not applicable.
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.). 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. PP3 is met if the REVEL score ≥ 0.7 or if the variant is predicted to impact splicing using SpliceAI score ≥0.5 Modification Type: General recommendation 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. Stand Alone Very Strong Strong Moderate Supporting To meet PP4, a congenital myopathy testing panel should be performed without identification of other causative variants and AT LEAST TWO of these features should be present Presence on Muscle Biopsy of: mini cores or central cores (histology or electron microscopy) Exercise, heat, or anesthetic induced rhabdomyolysis Ophthalmoplegia Characteristic muscle imaging (see Figure 8, Saade et al 2019 PMID: 31060725) 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 The minor allele frequency using the filtering allele frequency of either exomes or genomes of continental populations in gnomAD is ≥0.00697 for AR variants. All populations used should have at least 2000 alleles and >1 observation. BA1 exclusion variants (well-known pathogenic variants that are above the specified BA1 or BS1 threshold) are as follows: NM_000540.3:c.6721C>T (p.Arg2241Ter) NM_000540.3:c.10348-6C>G Modification Type: Disease-specific,Gene-specific Very Strong Strong Moderate Supporting Instructions: If the mode of inheritance for the variant is unclear (this largely applies to missense variants as loss of function variants are suspected to cause AR disease), use the more conservative AR cutoff and specifications for BA1. 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 The minor allele frequency using the filtering allele frequency of either exomes or genomes of continental populations in gnomAD is ≥0.0000006 for AR variants. All populations used should have at least 2000 alleles and >1 observation. BA1/BS1 exclusion variants (well-known pathogenic variants that are above the specified BA1 or BS1 threshold) are as follows: NM_000540.3:c.6721C>T (p.Arg2241Ter) NM_000540.3:c.10348-6C>G Modification Type: Disease-specific,Gene-specific Moderate Supporting Instructions: If the mode of inheritance for the variant is unclear (this largely applies to missense variants as loss of function variants are suspected to cause AR disease), use the more conservative AR cutoff and specifications for BS1. 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 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. Modification Type: No change Moderate No change - use as originally described Modification Type: No change Supporting No change - use as originally described Modification Type: No change 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: The VCEP has decided that lack of demonstrated effect in a functional assay should not count against the pathogenicity of an RYR1 variant because of the numerous possible functions of the ryanodine receptor; therefore all specified functional assays will only be used as evidence for pathogenicity.
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 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. Modification Type: No change Moderate No change - use as originally described Modification Type: No change Supporting No change - use as originally described Modification Type: No change 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: Both missense and truncating variants in RYR1 are disease-causing.
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 No change - use as originally described Modification Type: No change Moderate No change - use as originally described Modification Type: No change Supporting 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. Modification Type: No change Not Applicable
BP3 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary In frame-deletions/insertions in a repetitive region without a known function. Stand Alone Very Strong Strong Moderate Supporting Not Applicable Comments: There are no regions in RYR1 where BP3 would 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 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. BP4 is met if the REVEL score ≤ 0.15 or if the variant is not predicted to impact splicing using SpliceAI. Modification Type: General recommendation Not Applicable
BP5 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Variant found in a case with an alternate molecular basis for disease. Stand Alone Very Strong Strong No change - use as originally described Modification Type: No change Moderate No change - use as originally described Modification Type: No change Supporting Variant found in a case with an alternate molecular basis for disease. Modification Type: No change Not Applicable
BP6
Original ACMG Summary Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation. Not Applicable This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. PubMed : 29543229
BP7 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved. Stand Alone Very Strong Strong Moderate Supporting A synonymous variant for which SpliceAI predicts no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved. Modification Type: General recommendation Not Applicable

Rules for Combining Criteria

Pathogenic

1 Very Strong (PVS1, PS2_Very Strong, PM3_Very Strong) AND ≥ 1 Strong (PVS1_Strong, PS1, PS2, PS3, PM3_Strong, PM4_Strong, PM5_Strong, PM6_Strong, PP1_Strong)

1 Very Strong (PVS1, PS2_Very Strong, PM3_Very Strong) AND ≥ 2 Moderate (PVS1_Moderate, PS1_Moderate, PS2_Moderate, PM1, PM3, PM4, PM5, PM6, PP1_Moderate)

1 Very Strong (PVS1, PS2_Very Strong, PM3_Very Strong) AND 1 Moderate (PVS1_Moderate, PS1_Moderate, PS2_Moderate, PM1, PM3, PM4, PM5, PM6, PP1_Moderate) AND 1 Supporting (PVS1_Supporting, PS1_Supporting, PS2_Supporting, PS3_Supporting, PM2_Supporting, PM3_Supporting, PM4_Supporting, PM5_Supporting, PM6_Supporting, PP1, PP3, PP4)

1 Very Strong (PVS1, PS2_Very Strong, PM3_Very Strong) AND ≥ 2 Supporting (PVS1_Supporting, PS1_Supporting, PS2_Supporting, PS3_Supporting, PM2_Supporting, PM3_Supporting, PM4_Supporting, PM5_Supporting, PM6_Supporting, PP1, PP3, PP4)

≥ 2 Strong (PVS1_Strong, PS1, PS2, PS3, PM3_Strong, PM4_Strong, PM5_Strong, PM6_Strong, PP1_Strong)

1 Strong (PVS1_Strong, PS1, PS2, PS3, PM3_Strong, PM4_Strong, PM5_Strong, PM6_Strong, PP1_Strong) AND ≥ 3 Moderate (PVS1_Moderate, PS1_Moderate, PS2_Moderate, PM1, PM3, PM4, PM5, PM6, PP1_Moderate)

1 Strong (PVS1_Strong, PS1, PS2, PS3, PM3_Strong, PM4_Strong, PM5_Strong, PM6_Strong, PP1_Strong) AND 2 Moderate (PVS1_Moderate, PS1_Moderate, PS2_Moderate, PM1, PM3, PM4, PM5, PM6, PP1_Moderate) AND ≥ 2 Supporting (PVS1_Supporting, PS1_Supporting, PS2_Supporting, PS3_Supporting, PM2_Supporting, PM3_Supporting, PM4_Supporting, PM5_Supporting, PM6_Supporting, PP1, PP3, PP4)

1 Strong (PVS1_Strong, PS1, PS2, PS3, PM3_Strong, PM4_Strong, PM5_Strong, PM6_Strong, PP1_Strong) AND 1 Moderate (PVS1_Moderate, PS1_Moderate, PS2_Moderate, PM1, PM3, PM4, PM5, PM6, PP1_Moderate) AND ≥ 4 Supporting (PVS1_Supporting, PS1_Supporting, PS2_Supporting, PS3_Supporting, PM2_Supporting, PM3_Supporting, PM4_Supporting, PM5_Supporting, PM6_Supporting, PP1, PP3, PP4)

Likely Pathogenic

1 Very Strong (PVS1, PS2_Very Strong, PM3_Very Strong) AND 1 Moderate (PVS1_Moderate, PS1_Moderate, PS2_Moderate, PM1, PM3, PM4, PM5, PM6, PP1_Moderate)

1 Strong (PVS1_Strong, PS1, PS2, PS3, PM3_Strong, PM4_Strong, PM5_Strong, PM6_Strong, PP1_Strong) AND 1 Moderate (PVS1_Moderate, PS1_Moderate, PS2_Moderate, PM1, PM3, PM4, PM5, PM6, PP1_Moderate)

1 Strong (PVS1_Strong, PS1, PS2, PS3, PM3_Strong, PM4_Strong, PM5_Strong, PM6_Strong, PP1_Strong) AND ≥ 2 Supporting (PVS1_Supporting, PS1_Supporting, PS2_Supporting, PS3_Supporting, PM2_Supporting, PM3_Supporting, PM4_Supporting, PM5_Supporting, PM6_Supporting, PP1, PP3, PP4)

≥ 3 Moderate (PVS1_Moderate, PS1_Moderate, PS2_Moderate, PM1, PM3, PM4, PM5, PM6, PP1_Moderate)

2 Moderate (PVS1_Moderate, PS1_Moderate, PS2_Moderate, PM1, PM3, PM4, PM5, PM6, PP1_Moderate) AND ≥ 2 Supporting (PVS1_Supporting, PS1_Supporting, PS2_Supporting, PS3_Supporting, PM2_Supporting, PM3_Supporting, PM4_Supporting, PM5_Supporting, PM6_Supporting, PP1, PP3, PP4)

1 Moderate (PVS1_Moderate, PS1_Moderate, PS2_Moderate, PM1, PM3, PM4, PM5, PM6, PP1_Moderate) AND ≥ 4 Supporting (PVS1_Supporting, PS1_Supporting, PS2_Supporting, PS3_Supporting, PM2_Supporting, PM3_Supporting, PM4_Supporting, PM5_Supporting, PM6_Supporting, PP1, PP3, PP4)

1 Strong (PVS1_Strong, PS1, PS2, PS3, PM3_Strong, PM4_Strong, PM5_Strong, PM6_Strong, PP1_Strong) AND 2 Moderate (PVS1_Moderate, PS1_Moderate, PS2_Moderate, PM1, PM3, PM4, PM5, PM6, PP1_Moderate)

Benign

≥ 2 Strong (BS1, BS2, BS4, BP2_Strong, BP5_Strong)

1 Stand Alone (BA1)

Likely Benign

1 Strong (BS1, BS2, BS4, BP2_Strong, BP5_Strong) AND 1 Supporting (BS2_Supporting, BS4_Supporting, BP2, BP4, BP5, BP7)

≥ 2 Supporting (BS2_Supporting, BS4_Supporting, BP2, BP4, BP5, BP7)

Files & Images

PVS1 decision tree for RYR1:

PM3 chart:

References

1. Oza AM DiStefano MT et al. Expert specification of the ACMG/AMP variant interpretation guidelines for genetic hearing loss. Hum Mutat (2018) 39 (11) p. 1593-1613. 10.1002/humu.23630 30311386

2. Saade DN Neuhaus SB et al. The Use of Muscle Ultrasound in the Diagnosis and Differential Diagnosis of Congenital Disorders of Muscle in the Age of Next Generation Genetics. Semin Pediatr Neurol (2019) 29 p. 44-54. 10.1016/j.spen.2019.01.001 31060725

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