Variant: NM_000540.2(RYR1):c.6488G>C (p.Arg2163Pro)

CA024596

133159 (ClinVar)

Gene: RYR1

Condition: malignant hyperthermia, susceptibility to, 1

Inheritance Mode: Autosomal dominant inheritance

UUID: 63c8f3a1-4af0-4c9f-89c2-561a9a5354c2

Approved on: 2021-08-26

Published on: 2021-08-26

HGVS expressions

NM_000540.2:c.6488G>C
NM_000540.2(RYR1):c.6488G>C (p.Arg2163Pro)
NC_000019.10:g.38494565G>C
CM000681.2:g.38494565G>C
NC_000019.9:g.38985205G>C
CM000681.1:g.38985205G>C
NC_000019.8:g.43677045G>C
NG_008866.1:g.65866G>C
ENST00000599547.6:c.6488G>C
ENST00000359596.8:c.6488G>C
ENST00000355481.8:c.6488G>C
ENST00000359596.7:c.6488G>C
ENST00000360985.7:c.6485G>C
NM_001042723.1:c.6488G>C
NM_000540.3:c.6488G>C
NM_001042723.2:c.6488G>C

Likely Pathogenic

• Met criteria codes: PS4_Moderate PP1 PP3_Moderate PM1 PM5

• Not Met criteria codes: BP4 BA1 BS1

Expert Panel

Malignant Hyperthermia Susceptibility VCEP

Criteria Specification Information

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 arginine with proline at codon 2163 of the RYR1 protein, p.Arg2163Pro. This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in four unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, all 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_Moderate (PMID:10757649, PMID:20681998, PMID:24433488, PMID:31559918). This variant segregates with MHS in five individuals, PP1 (PMID:10757649). No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). Another variant has been assessed as pathogenic occurs at this codon, p.(Arg2163His), PM5. A REVEL score >0.85 (0.947) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as Likely Pathogenic. Criteria implemented: PS4_Moderate, PM1, PM5, PP3_Moderate, PP1.

Met criteria codes

• PS4_Moderate: This variant has been reported in four unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, all 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_Moderate (PMID:10757649, PMID:20681998, PMID:24433488, PMID:31559918).
• PP1: This variant segregates with MHS in five individuals PP1 (PMID:10757649).
• PP3_Moderate: A REVEL score >0.85 (0.947) supports a pathogenic status for this variant, PP3_Moderate.
• PM1: This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704).
• PM5: Another variant has been assessed as pathogenic occurs at this codon, p.(Arg2163His), PM5.

Not Met criteria codes

• BP4: 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
• BS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline