Submissions for variant NM_000540.3(RYR1):c.8519G>A (p.Arg2840Gln)

gnomAD frequency: 0.00001  dbSNP: rs923436076

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001197800	SCV001368579	uncertain significance	Congenital myopathy with fiber type disproportion	2020-04-02	criteria provided, single submitter	clinical testing	This variant was classified as: Uncertain significance. The available evidence favors the pathogenic nature of this variant, however the currently available data is insufficient to conclusively support its pathogenic nature. Thus this variant is classified as Uncertain significance - favor pathogenic. The following ACMG criteria were applied in classifying this variant: PM2,PP3.
All of Us Research Program, National Institutes of Health	RCV004010612	SCV004826032	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2024-02-05	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 2840 of the RYR1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual who died of a suspected malignant hyperthermia event and in his asymptomatic daughter, both without in vitro contracture test (PMID:35178478). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.