Variant: NM_000540.2(RYR1):c.1615T>C (p.Phe539Leu)

CA024297

133104 (ClinVar)

Gene: RYR1

Condition: malignant hyperthermia, susceptibility to, 1

Inheritance Mode: Autosomal dominant inheritance

UUID: 1f83c96d-f6ca-4543-aeaa-420f85809094

HGVS expressions

NM_000540.2:c.1615T>C
NM_000540.2(RYR1):c.1615T>C (p.Phe539Leu)
NC_000019.10:g.38455489T>C
CM000681.2:g.38455489T>C
NC_000019.9:g.38946129T>C
CM000681.1:g.38946129T>C
NC_000019.8:g.43637969T>C
NG_008866.1:g.26790T>C
ENST00000599547.6:n.1615T>C
ENST00000359596.8:c.1615T>C
ENST00000355481.8:c.1615T>C
ENST00000359596.7:n.1615T>C
ENST00000360985.7:c.1615T>C
NM_001042723.1:c.1615T>C
NM_000540.3:c.1615T>C
NM_001042723.2:c.1615T>C
NM_000540.3(RYR1):c.1615T>C (p.Phe539Leu)

Likely Pathogenic

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

• Met criteria codes: PM1 PS4_Moderate PP3_Moderate PP1

• Not Met criteria codes: BS1 BP4 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 phenylalanine with leucine at codon 539 of the RYR1 protein, p.Phe539Leu. This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in three individuals with a personal or family history of an MH episode, 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:30236257, PMID:18564801 (reported two individuals, may be related with shared haplotype)). This variant segregates with MHS with three informative meiosis, PP1_Supporting (PMID:18564801). 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). A REVEL score >0.85 (0.934) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Moderate, PM1, PP1_Supporting, PP3_Moderate.

Met criteria codes

• PM1: This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704).
• PS4_Moderate: This variant has been reported in three individuals with a personal or family history of an MH episode, 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:30236257, PMID:18564801 (reported two individuals, may be related with shared haplotype)).
• PP3_Moderate: A REVEL score >0.85 (0.934) supports a pathogenic status for this variant, PP3_Moderate.
• PP1: This variant segregates with MHS with three informative meiosis, PP1_Supporting (PMID:18564801).

Not Met criteria codes

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

Approved on: 2023-04-06

Published on: 2023-04-06