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Please note this is a beta version of the ClinGen Evidence Repository. This resource is intended to provide access to variant level evidence used and applied by ClinGen Variant Curation Expert Panels in the classification of variants. In this beta version, the evidence is limited to curation notes and referenced literature (PMIDs).

For general information about ClinGen Expert Panels and Variant Curation please visit: Clinical Domain Working Groups. For specific inquiries regarding a variant classification or evidence curation (e.g. population database queried, segregation counts or other evidence used) or to submit general comments about the evidence repo, please email us.

The resource is undergoing updates and tesing. Should you encounter any issues regarding the data displayed, lack of functionality or other problems, please let us know so we can rectify these accordingly. Your help in this regard is greatly appreciated.

ACMG variant classification Malignant Hyperthermia

Benign
Pathogenic
Stand Alone
Strong
Supporting
Supporting
Moderate
Strong
Very Strong
Population Data

Popmax allele frequency >0.0038 (0.38%) BA1

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 BS2

Popmax allele frequency >0.0008 (0.08%) BS1

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 historyb 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 PS4-Supporting

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 historyb 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 PS4-Moderate

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 areawarded 0.5 points, probands with a personal or family historyb 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 PS4

Computational And Predictive Data

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 BP7

Computational evidence suggest no impact on gene or gene product, REVEL score of <0.5 BP4

Multiple lines of computational evidence support a deleterious effect on the gene or gene product
•Use REVEL score of >0.85 PP3-Moderate

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 PM5

Same amino acid change as a previously established pathogenic variant regardless of nucleotide change
•Previously established pathogenic variant must reach a classification of pathogenicwithout PS1 PS1

Functional Data

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 BS3-Supporting

Located in a mutational hot spot and/or critical and well established functional domain
•Residues 4,631-4,991 (C-terminal region) PM1-Supporting

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 PS3-Supporting

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) PS3-Moderate

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) PM1

Well-established functional studies supportive of a damaging effect on protein function
•Knock-in mouse showing MH reaction in response to RYR1 agonist AND increasedsensitivity to RYR1 agonists in ex vivo tissue/cells PS3

Segregation Data

Co-segregation with disease in 3-4 reported meioses PP1


•Co-segregation with disease in 5-6 reported meioses PP1-Moderate

Co-segregation with disease in ≥7 reported meioses PP1-Strong

De novo Data

Each proven de novo case, 2 points, each assumed de novo case, 1 point, a total of 1 point PM6-Supporting

Each proven de novo case, 2 points, each assumed de novo case, 1 point, a total of 1 point PS2-Supporting

Each proven de novo case, 2 points, each assumed de novo case, 1 point, a total of 2-3 points PS2-Moderate

Each proven de novo case, 2 points, each assumed de novo case, 1 point, a total of 2-3 points PM6

Each proven de novo case, 2 points, each assumed de novo case, 1 point, a total of 4-7 points PM6-Strong

Each proven de novo case, 2 points, each assumed de novo case, 1 point, a total of 4-7 points PS2

Each proven de novo case, 2 points, each assumed de novo case, 1 point, ≥8 points PM6-Very Strong

Each proven de novo case, 2 points, each assumed de novo case, 1 point, ≥8 points PS2-Very Strong

Allelic Data

Observed in cis with a pathogenic variant in any inheritance pattern BP2

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