ClinVar

Description

Variant summary: RYR1 c.14203C>T (p.Arg4735Trp) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 277056 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in RYR1 causing Malignant Hyperthermia Susceptibility (4e-05 vs 8.8e-05), allowing no conclusion about variant significance. c.14203C>T has been reported in the literature in homozygous form, in case report, describing a newborn who had severe hypotonia, similar to some other patients with mutations at different loci in RYR1, however the patient also had cerebral atrophy and dysfunction, which is unusual for RYR1-related disorders (Gilfert 2016). This report therefore does not provide unequivocal conclusions about association of the variant with Malignant Hyperthermia Susceptibility (MHS). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. However, a study for a different missense change affecting the same amino acid (Arg4735Gln), showed pathological contractures after caffeine and halothane application, where the in vitro contracture tests were performed on a muscle biopsy specimen taken from a heterozygote patient with a history of clinical MH and a histology positive for central cores (Klingler 2014). In addition, some neighboring missense changes (p.Y4733D, p.G4734E, p.R4737Q, p.R4737W), have been reported in patients with malignant hyperthermia (HGMD). These data support the functional significance of this region. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.