Variant: NM_000540.3(RYR1):c.8327C>T (p.Ser2776Phe)

CA024910

197946 (ClinVar)

Gene: RYR1

Condition: malignant hyperthermia, susceptibility to, 1

Inheritance Mode: Autosomal dominant inheritance

UUID: b2a77c48-8743-48ea-ba30-0a6ef95a353d

HGVS expressions

NM_000540.3:c.8327C>T
NM_000540.3(RYR1):c.8327C>T (p.Ser2776Phe)
NC_000019.10:g.38505325C>T
CM000681.2:g.38505325C>T
NC_000019.9:g.38995965C>T
CM000681.1:g.38995965C>T
NC_000019.8:g.43687805C>T
NG_008866.1:g.76626C>T
ENST00000359596.8:c.8327C>T
ENST00000355481.8:c.8327C>T
ENST00000359596.7:n.8327C>T
ENST00000360985.7:c.8324C>T
ENST00000594335.5:n.1779C>T
NM_000540.2:c.8327C>T
NM_001042723.1:c.8327C>T
NM_001042723.2:c.8327C>T

Likely Benign

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

• Met criteria codes: BS1

• Not Met criteria codes: BP4 PS4 PS1 BA1 PP3 PM1 PM5

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 2776 of the RYR1 protein p.(Ser2776Phe). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.00145, this is considered to be more common than expected for a pathogenic variant causing autosomal dominant MHS, BS1. 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 (when the proband was unavailable for testing a positive diagnostic test result in a mutation positive relative was counted), ( PMID:21965348, PMID:30236257 ). 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 0.693 does not support a pathogenic or a benign status. This variant has been classified as Likely Benign. Criteria implemented: BS1.

Met criteria codes

• BS1: NFE maf in gnomAD 0.00145

Not Met criteria codes

• BP4: REVEL 0.693
• PS4: Two cases of MH reactions and positive IVCT, not counted due to NFE maf in gnomAD of 0.00145
• PS1: 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
• PP3: REVEL 0.693
• PM1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM5: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

Approved on: 2021-03-18

Published on: 2021-08-26