Variant: NM_000540.2(RYR1):c.5183C>T (p.Ser1728Phe)

133144 (ClinVar)

Gene: RYR1

Condition: malignant hyperthermia, susceptibility to, 1

Inheritance Mode: Autosomal dominant inheritance

UUID: 0aa6d960-500d-4088-884c-88858384a76a

Approved on: 2023-05-20

Published on: 2023-05-20

HGVS expressions

NM_000540.2:c.5183C>T
NM_000540.2(RYR1):c.5183C>T (p.Ser1728Phe)
NM_000540.3(RYR1):c.5183C>T (p.Ser1728Phe)

Likely Pathogenic

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

• Met criteria codes: PP1_Strong PS4 BP4

• Not Met criteria codes: PP3 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 Serine with Phenylalanine at codon 1728 of the RYR1 protein, p.(Ser1728Phe). The maximum allele frequency for this variant among the six major gnomAD populations is AMR: MAF 0.000029, a frequency consistent with pathogenicity for MHS. This variant has been reported in nine unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, nine 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; PMID:15731587). This variant segregates with MHS in five families, PP1_Strong (PMID:30236257). 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 <0.5 supports a benign status for this variant, BP4. Based on using Bayes to combine criteria this variant is assessed as Likely Pathogenic, (PMID: 29300386). Criteria implemented: PS4, PP1_Strong, BP4.

Met criteria codes

• PP1_Strong: This variant segregates with MHS in five families, PP1_Moderate (PMID:30236257).
• PS4: This variant has been reported in nine unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, nine 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; PMID:15731587).
• BP4: A REVEL score <0.5 supports a benign status for this variant, BP4.

Not Met criteria codes

• PP3: 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