Variant: NM_001042723.2:c.1630G>T

CA308123345

1210298 (ClinVar)

Gene: RYR1

Condition: malignant hyperthermia, susceptibility to, 1

Inheritance Mode: Autosomal dominant inheritance

UUID: b1f7b8ce-e9f5-4411-a4fb-ad1fd2f2ce6f

HGVS expressions

NM_001042723.2:c.1630G>T
NC_000019.10:g.38455504G>T
CM000681.2:g.38455504G>T
NC_000019.9:g.38946144G>T
CM000681.1:g.38946144G>T
NC_000019.8:g.43637984G>T
NG_008866.1:g.26805G>T
ENST00000599547.6:n.1630G>T
ENST00000359596.8:c.1630G>T
ENST00000355481.8:c.1630G>T
ENST00000359596.7:n.1630G>T
ENST00000360985.7:c.1630G>T
NM_000540.2:c.1630G>T
NM_001042723.1:c.1630G>T
NM_000540.3:c.1630G>T
NM_000540.3(RYR1):c.1630G>T (p.Asp544Tyr)

Likely Pathogenic

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

• Met criteria codes: PS4_Supporting PP1 PP3_Moderate PM1

• 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 aspartic acid with tyrosine at codon 544 of the RYR1 protein, p.Asp544Tyr. 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 who had a personal or family history of a malignant hyperthermia reaction, this individual 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_Supporting (PMID:19191329). 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). This variant segregates with MHS in four individuals, PP1_Supporting (PMID:19191329). A REVEL score >0.85 (0.924) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as Likely Pathogenic. Criteria implemented: PS4_Supporting, PM1, PP1_Supporting, PP3_Moderate.

Met criteria codes

• PS4_Supporting: This variant has been reported in an individual who had a personal or family history of a malignant hyperthermia reaction, this individual 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_Supporting (PMID:19191329).
• PP1: This variant segregates with MHS in four individuals, PP1_Supporting (PMID:19191329).
• PP3_Moderate: A REVEL score >0.85 (0.924) supports a pathogenic status for this variant, PP3_Moderate.
• PM1: This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704).

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