owencqueen/cgbench_data huggingface dataset:
Gene: RYR1 (HGNC:10483)
Evidence Code: PS1 — Strong
Modification Type: None
Same amino acid change as a previously established pathogenic variant regardless of nucleotide change




Previously established pathogenic variant must reach a classification of pathogenic without PS1
Gene: RYR1 (HGNC:10483)
Evidence Code: PS2 — Very Strong
Modification Type: Strength
Each proven de novo case, 2 points, each assumed de novo case, 1 point, ≥8 points
Gene: RYR1 (HGNC:10483)
Evidence Code: PS2 — Strong
Modification Type: Strength
Each proven de novo case, 2 points, each assumed de novo case, 1 point, a total of 4-7 points
Gene: RYR1 (HGNC:10483)
Evidence Code: PS2 — Moderate
Modification Type: Strength
Each proven de novo case, 2 points, each assumed de novo case, 1 point, a total of 2-3 points
Gene: RYR1 (HGNC:10483)
Evidence Code: PS2 — Supporting
Modification Type: Strength
Each proven de novo case, 2 points, each assumed de novo case, 1 point, a total of 1 point
Gene: RYR1 (HGNC:10483)
Evidence Code: PS3 — Strong
Modification Type: Strength,Disease-specific
Well-established functional studies supportive of a damaging effect on protein function




Knock-in mouse showing MH reaction in response to RYR1 agonist AND increased sensitivity to RYR1 agonists in ex vivo tisue/cells
Gene: RYR1 (HGNC:10483)
Evidence Code: PS3 — Moderate
Modification Type: Strength,Disease-specific
Well-established functional studies supportive of a damaging effect on protein function




Increased sensitivity to RYR1 agonist in HEK293 in vitro assay, Ca2+ release significantly increased compared to WT, controls to include known pathogenic and benign variants, n≥3.


Three or more independent ex vivo studies all showing release of Ca2+ in response to RYR1 agonist


Knock-in mouse showing MH reaction in response to RYR1 agonist OR increased sensitivity to RYR1 agonists in ex vivo tissue/cells (but not both, which would be PS3_strong)
Gene: RYR1 (HGNC:10483)
Evidence Code: PS3 — Supporting
Modification Type: Strength,Disease-specific
Well-established functional studies supportive of a damaging effect on protein function




Two independent ex vivo studies all showing release of Ca2+ in response to RYR1 agonist
Gene: RYR1 (HGNC:10483)
Evidence Code: PS4 — Strong
Modification Type: Strength,Disease-specific
The prevalence of the variant in affected individuals significantly increased compared with the prevalence in controls




≥7 MH case points. Probands with a personal or family history of an MH event are awarded 0.5 points, probands with a personal or family history of a positive (MHS)IVCT/CHCT are awarded an additional 0.5 points. Popmax in gnomAD ≤0.00006.


For variants with popmax MAF gnomAD >0.00006, an odds ratio of ≥18.7 when comparing MH case points to allele count in gnomAD can qualify. Popmax in gnomAD must be <0.0038.
Gene: RYR1 (HGNC:10483)
Evidence Code: PS4 — Moderate
Modification Type: Strength,Disease-specific
The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls




2-6 MH case points. Probands with a personal or family history of an MH event are awarded 0.5 points, probands with a personal or family history of a positive (MHS) IVCT/CHCT are awarded an additional 0.5 points. Popmax in gnomAD ≤0.00006


For variants with popmax MAF in gnomAD >0.00006, an odds ratio of ≥4.33 when comparing MH case points to allele count in gnomAD can qualify. Popmax in gnomAD must be <0.0038
Gene: RYR1 (HGNC:10483)
Evidence Code: PS4 — Supporting
Modification Type: Strength,Disease-specific
The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls




1 MH case point. Probands with a personal or family history of an MH event are awarded 0.5 points, probands with a personal or family history of a positive (MHS) IVCT/CHCT are awarded an additional 0.5 points. Popmax in gnomAD ≤0.00006


For variants with popmax MAF in gnomAD >0.00006, an odds ratio of ≥2.08 when comparing MH case points to allele count in gnomAD can qualify. Popmax in gnomAD must be <0.0038
Gene: RYR1 (HGNC:10483)
Evidence Code: PM1 — Moderate
Modification Type: Disease-specific
Located in a mutational hot spot and/or critical and well established functional domain




Residues 1-552 (N-terminal region) and 2,101-2,458 (central region)
Gene: RYR1 (HGNC:10483)
Evidence Code: PM1 — Supporting
Modification Type: Strength,Disease-specific
Located in a mutational hot spot and/or critical and well established functional domain




Residues 4,631-4,991 (C-terminal region)
Gene: RYR1 (HGNC:10483)
Evidence Code: PM5 — Moderate
Modification Type: None
Missense change at an amino acid residue where a different missense varaint previously determined to be pathogenic




Previously established pathogenic variant must reach a classification of pathogenicity without PM5


Grantham score for alternate pathogenic variant must be less than for variant being assessed
Gene: RYR1 (HGNC:10483)
Evidence Code: PM6 — Very Strong
Modification Type: Strength
Each proven de novo case, 2 points, each assumed de novo case, 1 point, ≥8 points
Gene: RYR1 (HGNC:10483)
Evidence Code: PM6 — Strong
Modification Type: Strength
Each proven de novo case, 2 points, each assumed de novo case, 1 point, a total of 4-7 points
Gene: RYR1 (HGNC:10483)
Evidence Code: PM6 — Moderate
Modification Type: Strength
Each proven de novo case, 2 points, each assumed de novo case, 1 point, a total of 2-3 points
Gene: RYR1 (HGNC:10483)
Evidence Code: PM6 — Supporting
Modification Type: Strength
Each proven de novo case, 2 points, each assumed de novo case, 1 point, a total of 1 point
Gene: RYR1 (HGNC:10483)
Evidence Code: PP1 — Strong
Modification Type: Strength
Co-segregation with disease in ≥7 reported meioses
Gene: RYR1 (HGNC:10483)
Evidence Code: PP1 — Moderate
Modification Type: Strength
Co-segregation with disease in 5-6 reported meioses
Gene: RYR1 (HGNC:10483)
Evidence Code: PP1 — Supporting
Modification Type: Strength
Co-segregation with disease in 3-4 reported meioses
Gene: RYR1 (HGNC:10483)
Evidence Code: PP3 — Moderate
Modification Type: Strength
Multiple lines of computational evidence support a deleterious effect on the gene or gene product




Use REVEL score of >0.85
Gene: RYR1 (HGNC:10483)
Evidence Code: BA1 — Stand Alone
Modification Type: Disease-specific
Popmax allele frequency >0.0038 (0.38%)
Gene: RYR1 (HGNC:10483)
Evidence Code: BS1 — Strong
Modification Type: Disease-specific
Popmax allele frequency >0.0008 (0.08%)
Gene: RYR1 (HGNC:10483)
Evidence Code: BS2 — Strong
Modification Type: Disease-specific
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.




Two or more variant positive individuals with a negative IVCT/CHCT test
Gene: RYR1 (HGNC:10483)
Evidence Code: BS2 — Moderate
Modification Type: Strength,Disease-specific
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.




One variant positive individual with a negative IVCT/CHCT test
Gene: RYR1 (HGNC:10483)
Evidence Code: BS3 — Moderate
Modification Type: Strength,Disease-specific
Well-established functional studies show no damaging effect on protein function




Three or more independent ex vivo studies, NO significant release of Ca2+ in response to agonist
Gene: RYR1 (HGNC:10483)
Evidence Code: BS3 — Supporting
Modification Type: Strength, Disease-specific
Well-established functional studies show no damaging effect on protein function




No significant increased sensitivity to RYR1 agonist in an approved in vitro assay, Ca2+ release measured, n≥3


One or two independent ex vivo studies, NO significant release of Ca2+ in response to agonist


Knock-in mouse showing no MH reaction in response to RYR1 agonist AND no increased sensitivity to RYR1 agonists in ex vivo tissue/cells
Gene: RYR1 (HGNC:10483)
Evidence Code: BP2 — Supporting
Modification Type: None
Observed in cis with a pathogenic variant in any inheritance pattern
Gene: RYR1 (HGNC:10483)
Evidence Code: BP4 — Supporting
Modification Type: Disease-specific
Computational evidence suggest no impact on gene or gene product, REVEL score of <0.5
Gene: RYR1 (HGNC:10483)
Evidence Code: BP7 — Supporting
Modification Type: None
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