Variant: NM_001042723.2:c.14349+1G>T

CA405685492

Gene: RYR1

Condition: malignant hyperthermia of anesthesia

Inheritance Mode: Autosomal dominant inheritance

UUID: cab80e3b-a64d-4f08-8022-ad44decbe4a4

HGVS expressions

NM_001042723.2:c.14349+1G>T
NC_000019.10:g.38578205G>T
CM000681.2:g.38578205G>T
NC_000019.9:g.39068845G>T
CM000681.1:g.39068845G>T
NC_000019.8:g.43760685G>T
NG_008866.1:g.149506G>T
ENST00000359596.8:c.14364+1G>T
ENST00000355481.8:c.14349+1G>T
ENST00000359596.7:n.14364+1G>T
ENST00000360985.7:c.14346+1G>T
NM_000540.2:c.14364+1G>T
NM_001042723.1:c.14349+1G>T
NM_000540.3:c.14364+1G>T

Uncertain Significance

• Met criteria codes: PS4_Supporting

• Not Met criteria codes: 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 guanine with thymine at position 14364+1 of the RYR1 cDNA, c.14364+1G>T. This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in an individual with a personal or family history of an MH episode and 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_Supporting (PMID: 25960145). No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. This variant is predicted to disrupt splicing, however, loss of function of RYR1 is not a common molecular etiology for MHS. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Supporting.

Met criteria codes

• PS4_Supporting: This variant has been reported in an individual with a personal or family history of an MH episode and 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_Supporting (PMID: 25960145).

Not Met criteria codes

• BA1: This variant was not present in a large population database (gnomAD) at the time this variant was interpreted.

Approved on: 2022-01-03

Published on: 2022-01-03