ClinVar

Description

Variant summary: RYR1 c.7076G>A (p.Arg2359Gln) results in a conservative amino acid change located in the RIH domain (IPR000699) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8.4e-06 in 239250 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.7076G>A has been reported in the literature in individuals affected with Malignant Hyperthermia Susceptibility, however without strong evidence for causality (e.g., Klingler_2014, Miller_2018). 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. The following publications have been ascertained in the context of this evaluation (PMID: 24433488, 30236257). Three ClinVar submitters (evaluation after 2014), including the ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, have cited the variant with conflicting assessments: two submitters (including the expert panel) classified the variant as likely pathogenic, and one submitter classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.