LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-10-30
Case ID: NM_000540.3_c.1840C_T_20261030_141531
Framework: ACMG/AMP 2015
Variant classification summary

NM_000540.3:c.1840C>T

RYR1  · NP_000531.2:p.(Arg614Cys)  · NM_000540.3
GRCh37: chr19:38948185 C>T  ·  GRCh38: chr19:38457545 C>T
Gene: RYR1 Transcript: NM_000540.3
Final call
VUS
PP3 moderate PP5 supporting
All criteria require review: For research and educational purposes only.
Variant details
Gene
RYR1
Transcript
NM_000540.3
Protein
NP_000531.2:p.(Arg614Cys)
gnomAD AF
7.310783901901671e-05 (v4.1)
ClinVar
Pathogenic
OncoKB
Classification rationale
Interpretation summary
Generated evidence synthesis
1
VUS: PP3 (moderate) is supported by REVEL 0.927 exceeding the VCEP threshold of 0.85.
2
VUS: PP5 (supporting) reflects the ClinGen RYR1 Expert Panel's pathogenic classification.
3
VUS: the applied evidence does not satisfy an ACMG/AMP 2015 pathogenic or benign combination rule.
Final determination: Under ACMG/AMP 2015 Table 5, one moderate pathogenic criterion plus one supporting pathogenic criterion does not meet a Pathogenic or Likely Pathogenic rule, so the classification is VUS.
Criteria assessment
ACMG/AMP criteria review
Criteria shown when status is available
All criteria require review: For research and educational purposes only.
Criterion Status Rationale Evidence used
PVS1 N/A Not applicable: the VCEP excludes PVS1 for this gene.
cspec
PS1 Not met Not met: no different nucleotide change producing the same pathogenic p.Arg614Cys amino-acid substitution was identified.
cspec clinvar
PS2 Not assessed Not assessed: no proven or assumed de novo case with sufficient parental-origin evidence is documented for RYR1 c.1840C>T.
cspec PMID:12411788 PMID:11668625
PS3 Not assessed Not assessed: one dyspedic-myotube study reports R614C hypersensitivity, but the VCEP requires either ≥3 HEK293 assays with controls, ≥3 independent ex vivo studies, or a knock-in mouse.
cspec PMID:12732639 PMID:11668625
PS4 Not assessed Not assessed: R614C occurs in 3 of 48 MH families, but no VCEP-required odds ratio and 95% confidence interval are available at popmax FAF 0.00007408.
cspec gnomad_v4 PMID:11668625 PMID:12411788 PMID:10484775 PMID:11493496 PMID:11553045
PM1 Not met Not met: residue 614 is outside all VCEP-specified PM1 regions, which are 1-552, 2,101-2,458, and 4,631-4,991.
cspec
PM2 N/A Not applicable: the RYR1 VCEP explicitly marks PM2 as not applicable.
cspec
PM3 N/A Not applicable: the VCEP excludes PM3 because malignant hyperthermia susceptibility is autosomal dominant with reduced penetrance.
cspec
PM4 N/A Not applicable: the VCEP excludes PM4 for this gene.
cspec
PM5 Not met Not met: zero qualifying alternate missense variants at RYR1 residue 614 were identified for comparison with p.Arg614Cys.
cspec pm5_candidates
PM6 Not assessed Not assessed: no case-level parental testing and clinical documentation establish an assumed de novo event for RYR1 c.1840C>T.
cspec
PP1 Not assessed Not assessed: available R614C family reports do not provide the exact 3-4 disease-cosegregating meioses required for VCEP Supporting PP1.
cspec PMID:12411788 PMID:11668625
PP2 N/A Not applicable: the RYR1 VCEP excludes PP2 because missense constraint is not established, with a gnomAD z-score of 1.92.
cspec
PP3 Met Met at moderate strength: REVEL 0.927 exceeds the VCEP's >0.85 threshold for deleterious computational evidence.
cspec revel
PP4 N/A Not applicable: the RYR1 VCEP excludes PP4 because CACNA1S variants also cause malignant hyperthermia susceptibility.
cspec
PP5 Met Not applicable: the RYR1 VCEP states that PP5 is not for use under the ClinGen Sequence Variant Interpretation VCEP Review Committee recommendation.
cspec clinvar
BA1 Not met Not met: the highest all-comers gnomAD popmax FAF is 0.00021229, below the VCEP BA1 threshold of >0.0038.
cspec gnomad_v2 gnomad_v4
BS1 Not met Not met: the highest all-comers gnomAD popmax FAF is 0.00021229, below the VCEP BS1 threshold of >0.0008.
cspec gnomad_v2 gnomad_v4
BS2 Not assessed Not assessed: no healthy adult R614C carrier with a negative IVCT/CHCT result is documented, although gnomAD reports zero homozygotes.
cspec PMID:12411788 gnomad_v2 gnomad_v4
BS3 Not assessed Not assessed: no study documents the VCEP-required absence of calcium release or agonist sensitivity in the specified in-vitro, ex-vivo, or knock-in-mouse conditions.
cspec PMID:12732639 PMID:11668625
BS4 N/A Not applicable: the RYR1 VCEP excludes BS4 because MHS phenotype determination is not sufficiently reliable for this criterion.
cspec
BP1 N/A Not applicable: the RYR1 VCEP states that malignant hyperthermia is caused primarily by missense variants.
cspec
BP2 Not assessed Not assessed: the only documented second-variant observation is trans compound heterozygosity, not the VCEP-required cis pathogenic-variant observation.
cspec PMID:12411788
BP3 N/A Not applicable: the VCEP excludes BP3 for this gene.
cspec
BP4 Not met Not met: REVEL 0.927 is above, not below, the VCEP's <0.5 threshold for no computational impact.
cspec revel
BP5 N/A Not applicable: the RYR1 VCEP excludes BP5 because MHS individuals have been described with two pathogenic RYR1 variants.
cspec
BP6 N/A Not applicable: the RYR1 VCEP states that BP6 is not for use under the ClinGen Sequence Variant Interpretation VCEP Review Committee recommendation.
cspec
BP7 N/A Not applicable: the variant is missense (p.Arg614Cys), whereas BP7 requires a synonymous (silent) variant.
cspec
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