The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

  • See Evidence submitted by expert panel for details.

Variant: NM_000540.3(RYR1):c.6617C>T (p.Thr2206Met)

CA024622

12977 (ClinVar)

Gene: RYR1
Condition: malignant hyperthermia, susceptibility to, 1
Inheritance Mode: Autosomal dominant inheritance
UUID: ecd64388-7fbd-43cd-8605-0d6feb7dbe20
Approved on: 2022-03-14
Published on: 2022-03-14

HGVS expressions

NM_000540.3:c.6617C>T
NM_000540.3(RYR1):c.6617C>T (p.Thr2206Met)
NC_000019.10:g.38496283C>T
CM000681.2:g.38496283C>T
NC_000019.9:g.38986923C>T
CM000681.1:g.38986923C>T
NC_000019.8:g.43678763C>T
NG_008866.1:g.67584C>T
ENST00000359596.8:c.6617C>T
ENST00000355481.8:c.6617C>T
ENST00000359596.7:n.6617C>T
ENST00000360985.7:c.6614C>T
ENST00000594335.5:n.69C>T
NM_000540.2:c.6617C>T
NM_001042723.1:c.6617C>T
NM_001042723.2:c.6617C>T
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Pathogenic

The Expert Panel has overridden the computationally generated classification - "Uncertain Significance - Conflicting Evidence"
Met criteria codes 7
PS3_Moderate BS2 PP3_Moderate PS4 PP1_Strong PM5 PM1_Supporting
Not Met criteria codes 2
BS1 BA1

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Malignant Hyperthermia Susceptibility VCEP
This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions. This sequence variant predicts a substitution of threonine with methionine at codon 2206 of the RYR1 protein, p.(Thr2206Met). The maximum allele frequency for this variant among the six major gnomAD populations is EAS: 0.00005, a frequency consistent with pathogenicity for MHS. This variant has been reported in 67 unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, 63 of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4 (PMID: 30236257, 12059893, 24433488, 23558838, 10484775, 25735680, 25960145, 16163667, 11575529, 12220451, 12434264, 15731587, 17081152, 18505122, 22696611, 9497245, 25268394, 31559918). This variant has been identified in at least three individuals with negative IVCT/CHCT results, BS2 (PMID: 30236257). Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists PS3_Moderate (PMID: 27586648). An ex vivo assay in patient derived myotubes from two related individuals showed an increased sensitivity to RYR1 agonists (PMID: 12220451). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, use PM1_Supporting to avoid overweighting with PM5 (PMID: 21118704). Another variant that has been assessed as pathogenic occurs at this codon, p.(Thr2206Arg), PM5. This variant segregates with MHS in nine individuals, PP1_Strong (PMID: 12059893, 25960145). A REVEL score >0.85 (0.95) supports a pathogenic status for this variant, PP3_Moderate. Based on using Bayes to combine criteria this variant is assessed as Pathogenic, (PMID: 29300386). Criteria implemented: PS4, PS3_Moderate, PM1_Supporting, PM5, PP1_Strong, PP3_Moderate, BS2.
Met criteria codes
PS3_Moderate
Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists PS3_Moderate (PMID: 27586648). An ex vivo assay in patient derived myotubes from two related individuals showed an increased sensitivity to RYR1 agonists (PMID: 12220451).
BS2
This variant has been identified in at least three individuals with negative IVCT/CHCT results, BS2 (PMID: 30236257).
PP3_Moderate
A REVEL score >0.85 (.95) supports a pathogenic status for this variant, PP3_Moderate.
PS4
This variant has been reported in 67 unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, 63 of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4 (PMID: 30236257, 12059893, 24433488, 23558838, 10484775, 25735680, 25960145, 16163667, 11575529, 12220451, 12434264, 15731587, 17081152, 18505122, 22696611, 9497245, 25268394, 31559918).
PP1_Strong
This variant segregates with MHS in nine individuals, PP1_Strong (PMID: 12059893, 25960145).
PM5
Another variant that has been assessed as pathogenic occurs at this codon, p.(Thr2206Arg), PM5.
PM1_Supporting
This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, use PM1_Supporting to avoid overweighting with PM5 (PMID: 21118704).
Not Met criteria codes
BS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
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