LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-11-01
Case ID: NM_000540.3_c.7300G_A_20261101_091527
Framework: ACMG/AMP 2015
Variant classification summary

NM_000540.3:c.7300G>A

RYR1  · NP_000531.2:p.(Gly2434Arg)  · NM_000540.3
GRCh37: chr19:38990633 G>A  ·  GRCh38: chr19:38499993 G>A
Gene: RYR1 Transcript: NM_000540.3
Final call
Likely Pathogenic
PS4 strong PM1 moderate 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.(Gly2434Arg)
gnomAD AF
9.665403555381524e-05 (v4.1)
ClinVar
Pathogenic
OncoKB
Classification rationale
Interpretation summary
Generated evidence synthesis
1
Pathogenic case enrichment: 7 MH case points and OR 738.94 satisfy the VCEP PS4 strong threshold.
2
Critical-region evidence: residue 2434 falls within the VCEP PM1 moderate region.
3
Computational evidence: REVEL 0.965 exceeds the VCEP PP3 cutoff.
4
Expert-panel evidence: ClinVar records a Pathogenic classification, supporting PP5.
Final determination: Under ACMG/AMP 2015 Table 5, one strong pathogenic criterion plus one to two moderate pathogenic criteria supports Likely Pathogenic; PS4 strong with PM1 and PP3 moderate satisfies this rule.
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 assessed Not assessed: reports use G7303A or Gly2435Arg nomenclature, but do not establish a distinct nucleotide variant from c.7300G>A for the same amino-acid change.
cspec PMID:10484775 PMID:10700782 PMID:11575529
PS2 Not assessed Not assessed: no proven or assumed de novo case with documented maternity and paternity testing is reported, so PS2 points cannot be assigned.
cspec
PS3 Not assessed Not assessed: one ex vivo study showed increased ryanodine-induced Ca2+ responses, but PS3 Supporting requires two independent ex vivo studies or another fully documented VCEP path.
cspec PMID:10700782 PMID:19648156 PMID:10484775
PS4 Met Met at strong: 7 MH case points and computed OR 738.94 (95% CI 337.82–1,616.35) exceed the VCEP's >=18.7 threshold with popmax FAF 0.00010959 <0.0038.
cspec PMID:10484775 PMID:11575529 PMID:11668625 PMID:23628358 gnomad_v4
PM1 Met Met at moderate: residue 2434 lies within the VCEP-approved central PM1 region 2,101-2,458, and PS1 or PM5 is not applied.
cspec
PM2 N/A Not applicable: the RYR1 VCEP marks PM2 not applicable and states that PM2 is not used alone.
cspec
PM3 N/A Not applicable: the VCEP excludes PM3 because MHS is autosomal dominant with reduced penetrance.
cspec
PM4 N/A Not applicable: the VCEP excludes PM4 for this gene.
cspec
PM5 Not assessed Not assessed: no different pathogenic missense comparator at residue 2434 was identified, so the required prior classification and Grantham-score comparison are unavailable.
cspec pm5_candidates
PM6 Not assessed Not assessed: no assumed de novo occurrence is documented, so the VCEP PM6 point total and strength cannot be calculated.
cspec
PP1 Not assessed Not assessed: cosegregation is described in selected families, but the number of qualifying reported meioses needed for PP1 strength is unavailable.
cspec PMID:11575529
PP2 N/A Not applicable: the RYR1 VCEP states that PP2 is not applicable because missense constraint is absent, with a gnomAD z-score of 1.92.
cspec
PP3 Met Met (moderate): REVEL 0.965 exceeds the VCEP's >0.85 threshold for computational evidence supporting a deleterious effect.
cspec revel
PP4 N/A Not applicable: the RYR1 VCEP explicitly marks PP4 as Not Applicable.
cspec
PP5 Met Not applicable: the RYR1 VCEP explicitly marks PP5 as Not Applicable.
cspec clinvar
BA1 Not met Not met: gnomAD v4.1 popmax FAF is 0.00010959 (0.010959%), below the VCEP BA1 threshold of >0.0038 (0.38%).
cspec gnomad_v4 gnomad_v2
BS1 Not met Not met: gnomAD v4.1 popmax FAF is 0.00010959 (0.010959%), below the VCEP BS1 threshold of >0.0008 (0.08%).
cspec gnomad_v4 gnomad_v2
BS2 Not assessed Not assessed: gnomAD reports zero homozygotes, but no qualifying healthy adult with a documented negative IVCT/CHCT test is available.
cspec gnomad_v4 gnomad_v2
BS3 Not met Not met: carrier myotubes had a 197-second versus 474-second Ca2+ response time, showing increased rather than absent ryanodine sensitivity.
cspec PMID:10700782
BS4 N/A Not applicable: the RYR1 VCEP does not use BS4 because MHS phenotype cannot be reliably determined without an MH crisis and IVCT has false positives.
cspec PMID:10484775
BP1 N/A Not applicable: the RYR1 VCEP states that malignant hyperthermia is caused primarily by missense variants, excluding BP1.
cspec
BP2 Not assessed Not assessed: no pathogenic variant in cis with p.Gly2434Arg or definitive cis-phase result is reported.
cspec
BP3 N/A Not applicable: the VCEP excludes BP3 for this gene.
cspec
BP4 Not met Not met: REVEL 0.965 does not satisfy the VCEP's <0.5 threshold for computational evidence suggesting no impact.
cspec revel
BP5 N/A Not applicable: the RYR1 VCEP explicitly marks BP5 as Not Applicable.
cspec
BP6 N/A Not applicable: the RYR1 VCEP explicitly marks BP6 as Not Applicable.
cspec
BP7 N/A Not applicable: the variant is missense, whereas the VCEP limits BP7 to synonymous variants.
cspec
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