Variant: NM_000540.3(RYR1):c.5036G>A (p.Arg1679His)

CA024479

161364 (ClinVar)

Gene: RYR1

Condition: malignant hyperthermia, susceptibility to, 1

Inheritance Mode: Autosomal dominant inheritance

UUID: 2a0fdcc4-215a-4abf-8c14-e8826949184d

Approved on: 2021-03-18

Published on: 2021-03-31

HGVS expressions

NM_000540.3:c.5036G>A
NM_000540.3(RYR1):c.5036G>A (p.Arg1679His)
NC_000019.10:g.38485691G>A
CM000681.2:g.38485691G>A
NC_000019.9:g.38976331G>A
CM000681.1:g.38976331G>A
NC_000019.8:g.43668171G>A
NG_008866.1:g.56992G>A
ENST00000355481.8:c.5036G>A
ENST00000359596.7:n.5036G>A
ENST00000360985.7:c.5033G>A
NM_000540.2:c.5036G>A
NM_001042723.1:c.5036G>A
NM_001042723.2:c.5036G>A

Likely Benign

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

• Met criteria codes: BS2_Supporting PP3_Moderate BS1

• Not Met criteria codes: BP4 PM1 PS3 PS4 BA1

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 Histidine at codon 1679 of the RYR1 protein, p.(Arg1679His). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.0022, this is considered to be more common than expected for a pathogenic variant causing autosomal dominantly inherited MHS, BS1. This variant has been reported in 2 unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, 2 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), (PMID:19346234, PMID:20142353). However, the high MAF in the NFE population in gnomAD precludes the use of PS4. This variant has been identified in an individual with negative IVCT/CHCT result, BS2_Moderate (PMID:19346234). A functional study was published for this variant using patient lymphocytes, this assay is not considered a standard assay by the ClinGen RYR1 VCEP for MHS (PMID:20142353). This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score >0.85 (0.918) supports a pathogenic status for this variant, PP3_Moderate. Based on using Bayes to combine criteria this variant is assessed as Likely Benign, (PMID: 29300386). Criteria implemented: BS1, BS2_Moderate, PP3_Moderate.

Met criteria codes

• BS2_Supporting: This variant has been identified in an individual with negative IVCT/CHCT result, BS2_Moderate (PMID:19346234).
• PP3_Moderate: A REVEL score >0.85 (0.918) supports a pathogenic status for this variant, PP3_Moderate.
• BS1: The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.0022, this is considered to be more common than expected for a pathogenic variant causing autosomal dominantly inherited MHS, BS1.

Not Met criteria codes

• BP4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS3: An ex vivo assay in lymphoblastoid B cells from a single patient showed an increased sensitivity to RYR1 agonists but this does not meet the criteria for PS3 which requires samples from multiple unrelated individuals to be tested, (PMID:20142353).
• PS4: This variant has been reported in two unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, both 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), (PMID:19346234, PMID:20142353). However, the high MAF in the NFE population in gnomAD precludes the use of PS4.
• BA1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline