rs147136339

Description

This sequence change replaces tyrosine with cysteine at codon 3933 of the RYR1 protein (p.Tyr3933Cys). The tyrosine residue is moderately conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is present in population databases (rs147136339, ExAC 0.1%). Three missense variants, p.Ile1571Val, p.Arg3366His, and p.Tyr3933Cys, which includes this variant (p.Tyr3933Cys), have been reported together in multiple individuals and families affected with RYR1-related disorders including malignant hyperthermia (MH) syndrome, congenital myopathy, central core disease (CCD), and multi minicore disease (MmD). In some cases, the phase of the three variants along with additional RYR1 variants was established, while in other cases it could not be determined. It is therefore unclear if one of the three variants or the additive effect of some or all of these mutations are causative for the RYR1-associated diseases in reported individuals (PMID: 25958340, 25735680, 25214167, 24950660, 25960145, 25658027, 21674524, 18564801, 20681998, 23558838, 30611313). ClinVar contains an entry for this variant (Variation ID: 133021). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Benign; Align-GVGD: Class C0). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Y3933C and R3366H reported in cis, and in conjunction with an additional RYR1 variant on the opposite allele, have been reported in patients with core myopathies as well as malignant hyperthermia susceptibility in some cases (Amburgey et al., 2013; Kraeva et al., 2015; Snoeck et al., 2015); Patients with only Y3933C and R3366H variants were reported to have malignant hyperthermia susceptibility or to be unaffected (Snoeck et al., 2015; Kraeva et al., 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32528171, 32403337, 32236737, 32125936, 31517061, 30932294, 25658027, 30611313, 30155738, 18564801, 25214167, 26332594, 28259615, 28269792, 25958340, 21674524, 22473935, 25735680, 23919265, 25960145, 20681998, 25637381, 30788618, 23558838, 24950660, 25747005, 24055113, 31321302)

PM1, PM2, PM3, PP2, PP3

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].