owencqueen/cgbench_data huggingface dataset:
Gene: RYR1 (HGNC:10483)
Evidence Code: 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.
Gene: RYR1 (HGNC:10483)
Evidence Code: PVS1 — Very Strong
Modification Type: Disease-specific,Gene-specific
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.
Gene: RYR1 (HGNC:10483)
Evidence Code: PVS1 — Strong
Modification Type: Gene-specific
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)
Gene: RYR1 (HGNC:10483)
Evidence Code: PVS1 — Moderate
Modification Type: Disease-specific,Gene-specific
See PVS1 flowchart
Gene: RYR1 (HGNC:10483)
Evidence Code: PVS1 — Supporting
Modification Type: Disease-specific,Gene-specific
See PVS1 flowchart
Gene: RYR1 (HGNC:10483)
Evidence Code: 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.
Gene: RYR1 (HGNC:10483)
Evidence Code: PS1 — Strong
Modification Type: No change
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.
Gene: RYR1 (HGNC:10483)
Evidence Code: PS1 — Moderate
Modification Type: No change
No change - use as originally described
Gene: RYR1 (HGNC:10483)
Evidence Code: PS1 — Supporting
Modification Type: No change
No change - use as originally described
Gene: RYR1 (HGNC:10483)
Evidence Code: 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.
Gene: RYR1 (HGNC:10483)
Evidence Code: PS2 — Very Strong
Modification Type: No change
No change - use as originally described
Gene: RYR1 (HGNC:10483)
Evidence Code: PS2 — Strong
Modification Type: No change
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.
Gene: RYR1 (HGNC:10483)
Evidence Code: PS2 — Moderate
Modification Type: No change
No change - use as originally described
Gene: RYR1 (HGNC:10483)
Evidence Code: PS2 — Supporting
Modification Type: No change
No change - use as originally described
Gene: RYR1 (HGNC:10483)
Evidence Code: 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.
Gene: RYR1 (HGNC:10483)
Evidence Code: PS3 — Strong
Modification Type: Disease-specific
Strong may only be considered for variant-specific mouse models. Currently, no other assays are applicable at this strength.
Gene: RYR1 (HGNC:10483)
Evidence Code: PS3 — Supporting
Modification Type: Gene-specific
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.
Gene: RYR1 (HGNC:10483)
Evidence Code: 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.
Gene: RYR1 (HGNC:10483)
Evidence Code: 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.
Gene: RYR1 (HGNC:10483)
Evidence Code: PM1 — Moderate
Modification Type: Disease-specific,Gene-specific
The pore/transmembrane region of RYR1 is critical for protein function and missense variants that fall within this region (amino acids 4800-4950)
Gene: RYR1 (HGNC:10483)
Evidence Code: 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.
Gene: RYR1 (HGNC:10483)
Evidence Code: PM2 — Supporting
Modification Type: Disease-specific,Gene-specific
PM2_Supporting may be applied if the minor allele frequency in population databases of at least 2000 alleles is 


 ≤ 0.00000697 for autosomal recessive
Gene: RYR1 (HGNC:10483)
Evidence Code: 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.
Gene: RYR1 (HGNC:10483)
Evidence Code: PM3 — Very Strong
Modification Type: Disease-specific,Gene-specific
4.0 points per the PM3 chart
Gene: RYR1 (HGNC:10483)
Evidence Code: PM3 — Strong
Modification Type: Disease-specific,Gene-specific
2.0 points per the PM3 chart
Gene: RYR1 (HGNC:10483)
Evidence Code: PM3 — Moderate
Modification Type: Disease-specific,Gene-specific
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
Gene: RYR1 (HGNC:10483)
Evidence Code: PM3 — Supporting
Modification Type: Disease-specific,Gene-specific
0.5 points per the PM3 chart
Gene: RYR1 (HGNC:10483)
Evidence Code: PM4 — Original ACMG Summary
Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.
Gene: RYR1 (HGNC:10483)
Evidence Code: PM4 — Strong
Modification Type: No change
No change - use as originally described
Gene: RYR1 (HGNC:10483)
Evidence Code: PM4 — Moderate
Modification Type: No change
Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.
Gene: RYR1 (HGNC:10483)
Evidence Code: PM4 — Supporting
Modification Type: No change
No change - use as originally described
Gene: RYR1 (HGNC:10483)
Evidence Code: 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.
Gene: RYR1 (HGNC:10483)
Evidence Code: PM5 — Strong
Modification Type: No change
No change - use as originally described
Gene: RYR1 (HGNC:10483)
Evidence Code: PM5 — Moderate
Modification Type: No change
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.
Gene: RYR1 (HGNC:10483)
Evidence Code: PM5 — Supporting
Modification Type: No change
No change - use as originally described
Gene: RYR1 (HGNC:10483)
Evidence Code: PM6 — Original ACMG Summary
Assumed de novo, but without confirmation of paternity and maternity.
Gene: RYR1 (HGNC:10483)
Evidence Code: PM6 — Strong
Modification Type: No change
No change - use as originally described
Gene: RYR1 (HGNC:10483)
Evidence Code: PM6 — Moderate
Modification Type: No change
Assumed de novo, but without confirmation of paternity and maternity.
Gene: RYR1 (HGNC:10483)
Evidence Code: PM6 — Supporting
Modification Type: No change
No change - use as originally described
Gene: RYR1 (HGNC:10483)
Evidence Code: 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.
Gene: RYR1 (HGNC:10483)
Evidence Code: PP1 — Strong
Modification Type: General recommendation
See segregation chart
Gene: RYR1 (HGNC:10483)
Evidence Code: PP1 — Moderate
Modification Type: General recommendation
See segregation chart
Gene: RYR1 (HGNC:10483)
Evidence Code: PP1 — Supporting
Modification Type: General recommendation
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
Gene: RYR1 (HGNC:10483)
Evidence Code: 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.
Gene: RYR1 (HGNC:10483)
Evidence Code: 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.
Gene: RYR1 (HGNC:10483)
Evidence Code: PP3 — Supporting
Modification Type: General recommendation
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
Gene: RYR1 (HGNC:10483)
Evidence Code: PP4 — Original ACMG Summary
Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.
Gene: RYR1 (HGNC:10483)
Evidence Code: PP4 — Supporting
Modification Type: Disease-specific,Gene-specific
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)
Gene: RYR1 (HGNC:10483)
Evidence Code: 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.
Gene: RYR1 (HGNC:10483)
Evidence Code: BA1 — Original ACMG Summary
Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
Gene: RYR1 (HGNC:10483)
Evidence Code: BA1 — Stand Alone
Modification Type: Disease-specific,Gene-specific
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
Gene: RYR1 (HGNC:10483)
Evidence Code: BS1 — Original ACMG Summary
Allele frequency is greater than expected for disorder.
Gene: RYR1 (HGNC:10483)
Evidence Code: BS1 — Strong
Modification Type: Disease-specific,Gene-specific
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
Gene: RYR1 (HGNC:10483)
Evidence Code: 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.
Gene: RYR1 (HGNC:10483)
Evidence Code: BS2 — Strong
Modification Type: No change
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.
Gene: RYR1 (HGNC:10483)
Evidence Code: BS2 — Moderate
Modification Type: No change
No change - use as originally described
Gene: RYR1 (HGNC:10483)
Evidence Code: BS2 — Supporting
Modification Type: No change
No change - use as originally described
Gene: RYR1 (HGNC:10483)
Evidence Code: BS3 — Original ACMG Summary
Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.
Gene: RYR1 (HGNC:10483)
Evidence Code: 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.
Gene: RYR1 (HGNC:10483)
Evidence Code: BS4 — Strong
Modification Type: No change
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.
Gene: RYR1 (HGNC:10483)
Evidence Code: BS4 — Moderate
Modification Type: No change
No change - use as originally described
Gene: RYR1 (HGNC:10483)
Evidence Code: BS4 — Supporting
Modification Type: No change
No change - use as originally described
Gene: RYR1 (HGNC:10483)
Evidence Code: BP1 — Original ACMG Summary
Missense variant in a gene for which primarily truncating variants are known to cause disease.
Gene: RYR1 (HGNC:10483)
Evidence Code: 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.
Gene: RYR1 (HGNC:10483)
Evidence Code: BP2 — Strong
Modification Type: No change
No change - use as originally described
Gene: RYR1 (HGNC:10483)
Evidence Code: BP2 — Moderate
Modification Type: No change
No change - use as originally described
Gene: RYR1 (HGNC:10483)
Evidence Code: BP2 — Supporting
Modification Type: No change
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.
Gene: RYR1 (HGNC:10483)
Evidence Code: BP3 — Original ACMG Summary
In frame-deletions/insertions in a repetitive region without a known function.
Gene: RYR1 (HGNC:10483)
Evidence Code: 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.
Gene: RYR1 (HGNC:10483)
Evidence Code: BP4 — Supporting
Modification Type: General recommendation
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.
Gene: RYR1 (HGNC:10483)
Evidence Code: BP5 — Original ACMG Summary
Variant found in a case with an alternate molecular basis for disease.
Gene: RYR1 (HGNC:10483)
Evidence Code: BP5 — Strong
Modification Type: No change
No change - use as originally described
Gene: RYR1 (HGNC:10483)
Evidence Code: BP5 — Moderate
Modification Type: No change
No change - use as originally described
Gene: RYR1 (HGNC:10483)
Evidence Code: BP5 — Supporting
Modification Type: No change
Variant found in a case with an alternate molecular basis for disease.
Gene: RYR1 (HGNC:10483)
Evidence Code: 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.
Gene: RYR1 (HGNC:10483)
Evidence Code: 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.
Gene: RYR1 (HGNC:10483)
Evidence Code: BP7 — Supporting
Modification Type: General recommendation
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.