Submissions for variant NM_000540.3(RYR1):c.4405C>T (p.Arg1469Trp)

gnomAD frequency: 0.00010  dbSNP: rs200546266

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000501380	SCV000596898	uncertain significance	not specified	2016-12-07	criteria provided, single submitter	clinical testing
GeneDx	RCV000520385	SCV000617748	pathogenic	not provided	2024-05-01	criteria provided, single submitter	clinical testing	Identified as heterozygous in individuals with susceptibility to malignant hyperthermia; however, these individuals also carried an additional RYR1 variant and detailed clinical and segregation information was not provided (PMID: 25735680, 25658027); 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: 25658027, 25637381, 26332594, 20839240, 31407473, 25735680, 30652412, 34463354, 27452334, 37937776, 31680123, 36939041)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000534955	SCV000659940	pathogenic	RYR1-related disorder	2024-01-25	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 1469 of the RYR1 protein (p.Arg1469Trp). This variant is present in population databases (rs200546266, gnomAD 0.03%). This missense change has been observed in individual(s) with clinical features of autosomal recessive congenital myopathy (PMID: 20839240, 21911697, 30652412, 31407473; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant has been reported in individual(s) with autosomal dominant malignant hyperthermia susceptibility (PMID: 25658027, 25735680); however, the role of the variant in this condition is currently unclear. ClinVar contains an entry for this variant (Variation ID: 161372). 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. For these reasons, this variant has been classified as Pathogenic.
PreventionGenetics, part of Exact Sciences	RCV000520385	SCV000852620	likely pathogenic	not provided	2017-05-12	criteria provided, single submitter	clinical testing
Cirak Lab, University Hospital Cologne	RCV000855482	SCV000996612	likely pathogenic	Fetal akinesia deformation sequence 1; Arthrogryposis multiplex congenita	2019-06-28	criteria provided, single submitter	research
CeGaT Center for Human Genetics Tuebingen	RCV000520385	SCV001151839	likely pathogenic	not provided	2019-07-01	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001198313	SCV001369197	likely pathogenic	Congenital myopathy with fiber type disproportion	2019-08-12	criteria provided, single submitter	clinical testing	This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PP2,PP3,BS2.
Revvity Omics, Revvity	RCV000520385	SCV002019113	likely pathogenic	not provided	2021-07-29	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000501380	SCV002511549	uncertain significance	not specified	2023-10-17	criteria provided, single submitter	clinical testing	Variant summary: RYR1 c.4405C>T (p.Arg1469Trp) results in a non-conservative amino acid change located in the B30.2/SPRY domain (IPR001870) of 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 0.00014 in 251126 control chromosomes. The observed variant frequency is approximately 51 fold of the estimated maximal expected allele frequency for a pathogenic variant in RYR1 causing Central Core Disease phenotype (2.8e-06), strongly suggesting that the variant is benign. c.4405C>T has been reported in the literature as isolated cases in a variety of clinical settings ranging from RYR1-related Congenital Myopathy with Central Nuclei (Wilmhurst_2010) or congenital fiber-type disproportion (Pinto_2022), Centronuclear myopathy (CNM) (Reumers_2021), Autosomal Recessive minicore myopathy (Krenn_2020), Fetal Akinesia/decreased fetal movement, pulmonary hypoplasia and AMC (Pergrande_2020, Alkhunaizi_2019), susceptibility to Malignant Hyperthermia/Rhabdomyolysis (example, Gillies_2015, Fiszer_2015, Kruijt_2021). The reported assertions range from Pathogenic/Likely pathogenic in settings of autosomal recessive minocore myopathy and Fetal Akinesia (Krenn_2020, Pergrande_2020) to VUS in settings of central core myopathy and Rhabdomyolysis susceptibility (example, Reumers_2021, Kruijt_2021). The association with susceptibility to malignant hyperthermia (MH) is also not clearly established based on this cross sectional review (example, Gillies_2015, Fiszer_2015) with at-least one report of a proband having no features of MH who carried this variant and c.10347+1G>A in the RYR1 gene (Alkhunaizi_2019). At least one co-occurrence with another pathogenic variant(s) supporting a diagnosis of Shprintzen-Goldberg syndrome have been observed in a patient undergoing exome sequencing at our laboratory (SKI c.100G>A, p.Gly34Ser), providing supporting evidence for an alternate molecular basis of disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 30652412, 25658027, 25735680, 31407473, 32978841, 31680123, 34463354, 20839240, 35548885). Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, classifying the variant as uncertain significance (n=1), likely pathogenic (n=6), or pathogenic (n=2). Based on the evidence outlined above, the variant was classified as uncertain significance.
Illumina Laboratory Services, Illumina	RCV000534955	SCV002540237	likely pathogenic	RYR1-related disorder	2022-01-12	criteria provided, single submitter	clinical testing	The RYR1 c.4405C>T (p.Arg1469Trp) missense variant results in the substitution of arginine at amino acid position 1469 with tryptophan. This variant has been reported in at least seven unrelated individuals (Klein et al. 2011; Maggi et al. 2013; Gillies et al. 2015; Fiszer et al. 2015; Alkhunaizi et al. 2019; Krenn et al. 2020). Five of the individuals had a clinical diagnosis of myopathy and two had malignant hyperthermia susceptibility (MHS). The individuals with myopathy were not reported to have MHS and had an additional variant in RYR1, which was detected in trans with the c.4405C>T variant in at least three individuals. The highest frequency of this allele in the Genome Aggregation Database is 0.000282 in the European (non-Finnish) population (version 2.1.1). Multiple lines of computational evidence suggest the variant may have a deleterious effect on the gene or gene product. Based on the available evidence, the c.4405C>T (p.Arg1469Trp) variant is classified as likely pathogenic for RYR1-related disorders.
All of Us Research Program, National Institutes of Health	RCV003998172	SCV004820838	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2023-12-18	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with tryptophan at codon 1469 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 been reported in two individuals affected with autosomal dominant malignant hyperthermia (PMID: 25658027, 25735680) and is associated with other phenotype(s) (ClinVar Variation ID: 161372). This variant has been identified in 36/251126 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Due to insufficient evidence, this variant is classified as a Variant of Uncertain Significance for autosomal dominant malignant hyperthermia.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV004017422	SCV004847590	likely pathogenic	Neuromuscular disease	2023-03-09	criteria provided, single submitter	clinical testing	The p.Arg1469Trp variant in RYR1 has been reported in 7 compound heterozygous probands who had either congenital myopathy, arthrogryposis, or minicore myopathy and segregated in at least 1 affected sibling (cis/trans not determined; Wilmshurst 2010 PMID: 20839240, Klein 2011 PMID: 21911697, Klein 2012 PMID: 22473935, Pergande 2020 PMID: 31680123, Alkhunaizi 2019 PMID: 30652412, Maggi 2013 PMID: 23394784, Krenn 2020 PMID: 31407473, Reumers 2021 PMID: 34463354). It has also been previously reported in 2 individuals with malignant hyperthermia (Fiszer 2015 PMID: 25658027, Gillies 2015 PMID: 25735680) and has been identified in ClinVar (Variation ID 161372). It has also been identified in 14/65346 (0.021%) European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that the p.Arg1469Trp variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive congenital myopathy. ACMG/AMP Criteria applied: PM3_VeryStrong, PP4, PP3.
CSER _CC_NCGL, University of Washington	RCV000148819	SCV000190558	uncertain significance	Congenital myopathy	2014-06-01	no assertion criteria provided	research
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000520385	SCV001927858	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000520385	SCV001953100	uncertain significance	not provided		no assertion criteria provided	clinical testing