ClinVar

Description

Variant summary: RYR1 c.9859C>T (p.Arg3287Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0001 in 280070 control chromosomes (gnomAD), predominantly at a frequency of 0.0011 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 13 fold of the estimated maximal expected allele frequency for a pathogenic variant in RYR1 causing Malignant Hyperthermia Susceptibility phenotype (8.8e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.9859C>T has been reported in the literature in individuals without history of adverse anesthetic events (van den Bersselaar_2022) and in an individual affected with congenital myopathy (Gonorazky_2019). These reports do not provide unequivocal conclusions about association of the variant with Malignant Hyperthermia Susceptibility. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters have assessed the variant since 2014: both classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.