ClinVar Genomic variation as it relates to human health

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 Histidine at codon 4505 of the RYR1 protein, p.(Asp4505His). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.0054, which is considered to be too common for a pathogenic variant causing autosomal dominantly inherited MHS, BA1. This variant has been classified as Benign. Criteria implemented: BA1.

This variant is associated with the following publications: (PMID: 18813041, 23476141, 27147545, 23394784, 22473935, 24195946, 23329375, 25735680, 21918424, 27153395, 26332594, 27058611, 27663056, 28326467, 26019235, 30842289, 32381029)

Variant summary: RYR1 c.13513G>C (p.Asp4505His) results in a non-conservative amino acid change located in the ryanodine receptor TM 4-6 domain (IPR009460) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0034 in 206460 control chromosomes, including 2 homozygotes, and predominantly at a frequency of 0.0054 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is higher than the estimated maximal expected allele frequency for a pathogenic variant in RYR1 causing Malignant Hyperthermia Susceptibility phenotype determined by the ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel (0.0054 vs 0.0038; Johnston_2021), suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.13513G>C has been reported in the literature in individuals affected with malignant hyperthermia susceptibility, King-Denborough syndrome, congenital myopathy, RYR1-related late-onset axial myopathy, core myopathy, idiopathic hyperCKemia and atrioventricular septal defect; however no strong evidences of pathogenicity were found in these studies (e.g. Malandrini_2008, Groom_2011, Klein_2012, Maggi_2013, Loseth_2013, Klingler_2014, Gillies_2015, Priest_2016, Jokela_2019, Elliott_2022, Fusto_2022). Thus, these reports do not provide unequivocal conclusions about association of the variant with Malignant Hyperthermia Susceptibility or other RYR2-related disorders. This variant was found to cause a modest increase in caffeine sensitivity as compared to the wild type protein, and to further enhance such sensitivity when present in cis or trans with another variant, p.R3983C (Groom_2011). Twelve submitters, including the ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, have provided clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as benign (n=2)/likely benign (n=6) or VUS (n=4). Based on the evidence outlined above, the variant was classified as likely benign.

RYR1: BS1, BS2

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.