Variant: NM_000540.2(RYR1):c.10100A>G (p.Lys3367Arg)

CA023815

65956 (ClinVar)

Gene: RYR1

Condition: malignant hyperthermia, susceptibility to, 1

Inheritance Mode: Autosomal dominant inheritance

UUID: 824d3211-edc0-43c2-a2ac-734a25134ae6

Approved on: 2021-05-27

Published on: 2021-05-27

HGVS expressions

NM_000540.2:c.10100A>G
NM_000540.2(RYR1):c.10100A>G (p.Lys3367Arg)
NC_000019.10:g.38519295A>G
CM000681.2:g.38519295A>G
NC_000019.9:g.39009935A>G
CM000681.1:g.39009935A>G
NC_000019.8:g.43701775A>G
NG_008866.1:g.90596A>G
ENST00000359596.8:c.10100A>G
ENST00000355481.8:c.10100A>G
ENST00000359596.7:n.10100A>G
ENST00000360985.7:c.10097A>G
ENST00000594335.5:n.3502A>G
ENST00000599547.5:n.907A>G
NM_001042723.1:c.10100A>G
NM_000540.3:c.10100A>G
NM_001042723.2:c.10100A>G

Likely Benign

The Expert Panel has overridden the computationally generated classification - "Uncertain Significance - Insufficient Evidence"

• Met criteria codes: BS3_Supporting

• Not Met criteria codes: PP3 PS4

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 lysine with arginine at codon 3367 of the RYR1 protein, p.(Lys3367Arg). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in an individual with a personal or family history of an MH episode without an in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (PMID:16732084). Functional studies in HEK293 cells do not show an increased sensitivity to RYR1 agonists, BS3_Supporting (PMID:32535660). A REVEL score of 0.632 supports neither a pathogenic nor a benign status for this variant. Based on using Bayes to combine criteria this variant is assessed as Likely Benign, (PMID: 29300386). Criteria implemented: BS3_Supporting.

Met criteria codes

• BS3_Supporting: Functional studies in HEK293 cells do not show an increased sensitivity to RYR1 agonists, BS3_Supporting (PMID:32535660).

Not Met criteria codes

• PP3: A REVEL score of 0.632 supports neither a pathogenic nor a benign status for this variant.
• PS4: This variant has been reported in an individual with a personal or family history of an MH episode without an in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (PMID:16732084).