Variant: NM_000540.2(RYR1):c.11958C>G (p.Asp3986Glu)

CA023951

133026 (ClinVar)

Gene: RYR1

Condition: malignant hyperthermia, susceptibility to, 1

Inheritance Mode: Autosomal dominant inheritance

UUID: 71a97107-eb35-424a-b0bd-22b0f158fe29

Approved on: 2022-09-08

Published on: 2022-09-08

HGVS expressions

NM_000540.2:c.11958C>G
NM_000540.2(RYR1):c.11958C>G (p.Asp3986Glu)
NC_000019.10:g.38543821C>G
CM000681.2:g.38543821C>G
NC_000019.9:g.39034461C>G
CM000681.1:g.39034461C>G
NC_000019.8:g.43726301C>G
NG_008866.1:g.115122C>G
ENST00000688602.1:n.368C>G
ENST00000689936.1:n.350C>G
ENST00000359596.8:c.11958C>G
ENST00000355481.8:c.11943C>G
ENST00000359596.7:n.11958C>G
ENST00000360985.7:c.11940C>G
ENST00000593322.1:n.567C>G
ENST00000594335.5:n.5327C>G
NM_001042723.1:c.11943C>G
NM_000540.3:c.11958C>G
NM_001042723.2:c.11943C>G
NM_000540.3(RYR1):c.11958C>G (p.Asp3986Glu)

Uncertain Significance

• Met criteria codes: PS4 PP1 BS3_Supporting

• Not Met criteria codes: BS1 BP4 BA1 PP3 PM1

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 glutamic acid at codon 3986 of the RYR1 protein, p.(Asp3986Glu). This variant is not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in ten unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, 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 (PMID:30236257; PMID:23558838). Functional studies in HEK293 cells do not show an increased sensitivity to RYR1 agonists, BS3_Supporting (PMID: 28403410). This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. This variant segregates with MHS in four individuals/families, PP1_Supporting (PMID:28403410). A REVEL score of 0.763 supports neither a pathogenic nor a benign status for this variant. Based on using Bayes to combine criteria this variant is assessed as Variant of Unknown Significance (PMID: 29300386). Criteria implemented: PS4, BS3_Supporting, PP1.

Met criteria codes

• PS4: This variant has been reported in ten unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, 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 (PMID:30236257; PMID:23558838).
• PP1: This variant segregates with MHS in four individuals/families, PP1_Supporting ( PMID:28403410).
• BS3_Supporting: Functional studies in HEK293 cells do not show an increased sensitivity to RYR1 agonists, BS3_Supporting (PMID: 28403410).

Not Met criteria codes

• BS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP4: A REVEL score of 0.763 supports neither a pathogenic nor a benign status for this variant.
• BA1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP3: A REVEL score of 0.763 supports neither a pathogenic nor a benign status for this variant.
• PM1: This variant does not reside in a hotspot for pathogenic variants that contribute to MHS.