ClinVar Miner

Submissions for variant NM_000540.3(RYR1):c.7093G>A (p.Gly2365Arg)

gnomAD frequency: 0.00003  dbSNP: rs761224660
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Clinical Genetics and Genomics, Karolinska University Hospital RCV001269584 SCV001449675 likely pathogenic not provided 2017-02-21 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001342175 SCV001536087 uncertain significance RYR1-related disorder 2023-12-30 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 2365 of the RYR1 protein (p.Gly2365Arg). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with autosomal recessive centronuclear myopathy (PMID: 28818389). 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 clinical features of autosomal dominant central core disease (PMID: 25214167; Invitae); however, the role of the variant in this condition is currently unclear. ClinVar contains an entry for this variant (Variation ID: 561101). 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 with a positive predictive value of 95%. 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.
GeneDx RCV001269584 SCV001778339 uncertain significance not provided 2021-03-29 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Observed in the heterozygous state in at least two individuals with features of RYR1-related disorder, but one individual had limited clinical information provided and only a benign RYR1 variant identified as a second variant, whereas the other individual also had a splicing variant in RYR1, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes (Savarese et al., 2014; Fattori et al., 2015; Abath Neto et al., 2017) This variant is associated with the following publications: (PMID: 25326635, 28818389, 25957634, 25214167)
Mayo Clinic Laboratories, Mayo Clinic RCV001269584 SCV004224629 uncertain significance not provided 2022-10-07 criteria provided, single submitter clinical testing PP3, PM2
All of Us Research Program, National Institutes of Health RCV004004221 SCV004843750 uncertain significance Malignant hyperthermia, susceptibility to, 1 2023-12-01 criteria provided, single submitter clinical testing
Muscle and Diseases Team, Institut de Génétique et Biologie Moléculaire et Cellulaire RCV004586875 SCV005038488 likely pathogenic Centronuclear myopathy 2024-03-01 criteria provided, single submitter research PM1+PM2+PM3+PP1+PP2+PP3+PP5
Muscle and Diseases Team, Institut de Génétique et Biologie Moléculaire et Cellulaire RCV004586876 SCV005038614 pathogenic RYR1-related myopathy 2024-03-01 criteria provided, single submitter research PM3_Strong+PM1+PM2+PP2+PP3+PP5
Baylor Genetics RCV000680087 SCV000807527 uncertain significance Congenital multicore myopathy with external ophthalmoplegia 2017-09-01 flagged submission clinical testing Likely pathogenicity based on finding it once in our laboratory in trans with a pathogenic variant in a 13-year-old female with hypotonia, myopthic facies, scoliosis, joint hyperlaxity, apnea, recurrent pneumonia, ophthalmoparesis, two sibling deceased in infancy due to respiratory failure

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