Submissions for variant NM_000540.3(RYR1):c.821G>C (p.Arg274Pro)

gnomAD frequency: 0.00003  dbSNP: rs368711923

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000655561	SCV000777492	uncertain significance	RYR1-related disorder	2022-02-18	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 274 of the RYR1 protein (p.Arg274Pro). This variant is present in population databases (rs368711923, gnomAD 0.05%). This missense change has been observed in individual(s) with clinical features of RYR1-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 544424). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt RYR1 protein function. 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.
PreventionGenetics, part of Exact Sciences	RCV000721700	SCV000852828	uncertain significance	not provided	2016-04-25	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001334525	SCV001527393	uncertain significance	Central core myopathy	2018-09-07	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Fulgent Genetics, Fulgent Genetics	RCV002485488	SCV002777162	uncertain significance	Central core myopathy; Malignant hyperthermia, susceptibility to, 1; Congenital multicore myopathy with external ophthalmoplegia; Congenital myopathy with fiber type disproportion; King Denborough syndrome	2021-08-09	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004004147	SCV004814426	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2024-02-05	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with proline at codon 274 of the RYR1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with RYR1-related disorders in the literature. This variant has been identified in 12/278392 chromosomes 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.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000721700	SCV001809049	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000721700	SCV001964089	uncertain significance	not provided		no assertion criteria provided	clinical testing