Variant: NM_000540.3(RYR1):c.4711A>G (p.Ile1571Val)

CA024455

159851 (ClinVar)

Gene: RYR1

Condition: malignant hyperthermia, susceptibility to, 1

Inheritance Mode: Autosomal dominant inheritance

UUID: 7e5308e9-be2e-421c-9452-621eebb03784

HGVS expressions

NM_000540.3:c.4711A>G
NM_000540.3(RYR1):c.4711A>G (p.Ile1571Val)
NC_000019.10:g.38483293A>G
CM000681.2:g.38483293A>G
NC_000019.9:g.38973933A>G
CM000681.1:g.38973933A>G
NC_000019.8:g.43665773A>G
NG_008866.1:g.54594A>G
ENST00000355481.8:c.4711A>G
ENST00000359596.7:n.4711A>G
ENST00000360985.7:c.4708A>G
NM_000540.2:c.4711A>G
NM_001042723.1:c.4711A>G
NM_001042723.2:c.4711A>G

Likely Benign

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

• Met criteria codes: BS1

• Not Met criteria codes: PM1 BA1 BP4 PS4 PP3

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 Isoleucine with Valine at codon 1571 of the RYR1 protein, p.(Ile1571Val). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.0014, 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 five 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), (PMID:25958340, PMID:20681998, PMID:25658027, PMID:25735680). However, the high MAF in the NFE population in gnomAD precludes the use of PS4. No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score of 0.56 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: BS1. 

Met criteria codes

• BS1: MAF > 0.0008 in NFE population.

Not Met criteria codes

• PM1: 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
• BP4: A REVEL score of 0.56 supports neither a pathogenic nor a benign status for this variant.
• PS4: This variant has been reported in five 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), (PMID:25958340, PMID:20681998, PMID:25658027, PMID:25735680). However, the high MAF in the NFE population in gnomAD precludes the use of PS4.
• PP3: A REVEL score of 0.56 supports neither a pathogenic nor a benign status for this variant.

Approved on: 2021-03-18

Published on: 2021-03-31