Submissions for variant NM_000540.3(RYR1):c.325C>T (p.Arg109Trp)

gnomAD frequency: 0.00005  dbSNP: rs118192173

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000119608	SCV000194822	likely pathogenic	not provided	2013-11-07	criteria provided, single submitter	clinical testing
Invitae	RCV000655512	SCV000777443	pathogenic	RYR1-related disorder	2023-12-22	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 109 of the RYR1 protein (p.Arg109Trp). This variant is present in population databases (rs118192173, gnomAD 0.01%). This missense change has been observed in individual(s) with autosomal recessive congenital myopathy (PMID: 23826317, 28357410; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12988). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RYR1 protein function. Experimental studies have shown that this missense change affects RYR1 function (PMID: 18171678). For these reasons, this variant has been classified as Pathogenic.
PreventionGenetics, part of Exact Sciences	RCV000655512	SCV000852564	pathogenic	RYR1-related disorder	2023-12-31	criteria provided, single submitter	clinical testing	The RYR1 c.325C>T variant is predicted to result in the amino acid substitution p.Arg109Trp. This variant has been reported in individuals with autosomal recessive core myopathy (Zhou et al. 2006. PubMed ID: 16940308; Abath Neto et al. 2017. PubMed ID: 28818389; Matthews et al. 2018. PubMed ID: 29298851; Table S1, Natera-de Benito et al. 2020. PubMed ID: 33333461). This variant is reported in 0.012% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant has been classified as pathogenic or likely pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/12988/). This variant is interpreted as pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000119608	SCV001248774	pathogenic	not provided	2019-09-01	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001199051	SCV001370046	likely pathogenic	Congenital myopathy with fiber type disproportion	2019-11-19	criteria provided, single submitter	clinical testing	This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2,PP3.
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000119608	SCV001450338	likely pathogenic	not provided	2017-01-03	criteria provided, single submitter	clinical testing
GeneDx	RCV000119608	SCV001983919	pathogenic	not provided	2022-09-27	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: R109W expressed in the homozygous state results in complete loss of calcium conductance (Zhou et al., 2006); Not observed at significant frequency in large population cohorts (gnomAD); 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: 29298851, 23553787, 17483490, 17365175, 18171678, 27858727, 28818389, 28357410, 16380615, 30155738, 30611313, 31127727, 33646172, 33646171, 32381029, 17033962, 34463354, 31589614, 32528171, 35361824, 27535533, 23826317, 24195946, 28547000, 22473935, 27855725, 23069638, 16084090, 33333461, 33726816, 16940308)
Revvity Omics, Revvity	RCV000119608	SCV002019944	pathogenic	not provided	2023-12-15	criteria provided, single submitter	clinical testing
AiLife Diagnostics, AiLife Diagnostics	RCV000119608	SCV002501075	likely pathogenic	not provided	2021-05-26	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002496350	SCV002807461	pathogenic	Central core myopathy; Malignant hyperthermia, susceptibility to, 1; Congenital multicore myopathy with external ophthalmoplegia; Congenital myopathy with fiber type disproportion; King Denborough syndrome	2021-11-22	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV003447473	SCV004175376	likely pathogenic	Central core myopathy	2022-04-08	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV003447473	SCV004807515	pathogenic	Central core myopathy	2024-03-29	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003996093	SCV004820712	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2024-01-11	criteria provided, single submitter	clinical testing	This pathogenicity assessment is for autosomal dominant malignant hyperthermia susceptibility phenotype. This missense variant replaces arginine with tryptophan at codon 109 of the RYR1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 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 malignant hyperthermia susceptibility. This variant has been reported to segregate with autosomal recessive congenital myopathy in several families and has been reported in multiple unrelated individuals affected with congenital myopathy (PMID: 16940308, 23826317, 28357410, 22473935). This variant has been identified in 22/282604 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.
Muscle and Diseases Team, Institut de Génétique et Biologie Moléculaire et Cellulaire	RCV004586005	SCV005038491	pathogenic	Centronuclear myopathy	2024-03-01	criteria provided, single submitter	research	PM3_Strong+PM2+PM5+PP1+PP2+PP3
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000119608	SCV005196814	pathogenic	not provided	2023-10-03	criteria provided, single submitter	clinical testing
OMIM	RCV000013860	SCV000034107	pathogenic	Congenital multicore myopathy with external ophthalmoplegia	2012-06-01	no assertion criteria provided	literature only
Leiden Muscular Dystrophy (RYR1)	RCV000119608	SCV000154515	not provided	not provided		no assertion provided	not provided