ClinVar Miner

Submissions for variant NM_000540.2(RYR1):c.7025A>G (p.Asn2342Ser) (rs147213895)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000148811 SCV000265721 likely benign Malignant hyperthermia, susceptibility to, 1 2013-07-01 criteria provided, single submitter research
CSER_CC_NCGL; University of Washington Medical Center RCV000148811 SCV000190550 uncertain significance Malignant hyperthermia, susceptibility to, 1 2014-06-01 no assertion criteria provided research
CeGaT Praxis fuer Humangenetik Tuebingen RCV000119674 SCV000575173 uncertain significance not provided 2018-09-30 criteria provided, single submitter clinical testing
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000119674 SCV000609897 uncertain significance not provided 2017-05-12 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000119674 SCV000203455 uncertain significance not provided 2014-03-21 criteria provided, single submitter clinical testing
GeneDx RCV000119674 SCV000565503 uncertain significance not provided 2018-09-07 criteria provided, single submitter clinical testing The c.7025 A>G variant in the RYR1 gene was initially reported in an individual who had an episode of malignant hyperthermia under anesthesia, and a positive in-vitro contracture test (IVCT) on muscle (Marchant et al., 2004). However, this variant was also found not to segregate with malignant hyperthermia susceptibility in another family as it was identified in an individual with a negative IVCT (Marchant et al., 2004). Subsequent publications are conflicting regarding the pathogenicity of this variant (Gonsalves et al., 2013; Zullo et al., 2009) and multiple publications classify c.7025 A>G as a variant of uncertain significance (Brandom et al., 2013; Dorschner et al., 2013). The c.7025 A>G variant is observed in 285/277120 (0.1%) global alleles from individuals in large population cohorts (Lek et al., 2016). In-silico splice models predict that c.7025 A>G may create a cryptic splice acceptor site in intron 42 that could supplant the natural splice acceptor site. However, in the absence of RNA/functional studies, the actual effect of the c.7025 A>G change in this individual is unknown. If c.7025 A>G does not alter splicing, it will result in the N2342S missense change. This variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. We interpret c.7025 A>G as a variant of uncertain significance.
Illumina Clinical Services Laboratory,Illumina RCV000325643 SCV000412390 likely benign Malignant hyperthermia susceptibility 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV000530570 SCV000660011 uncertain significance RYR1-Related Disorders 2018-12-31 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 2342 of the RYR1 protein (p.Asn2342Ser). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and serine. This variant is present in population databases (rs147213895, ExAC 0.2%). This variant has been reported in individuals and families affected with malignant hyperthermia susceptibility (MHS) (PMID: 15221887, 23558838, 25960145, 24433488, 28224104). Although this variant was reported to segregate with MHS in two families, the number of affected individuals in these families was unavailable. In addition, this variant did not segregate with MHS in one family (PMID: 15221887). This variant has also been identified in patients affected with central core disease (CCD) and late-onset axial myopathy (PMID: 25960145, 3329375). ClinVar contains an entry for this variant (Variation ID: 133175). Experimental studies performed on patient-derived cells carrying this variant have shown that this missense change leads to altered RYR1 activity (PMID: 19191333). This missense change is located in a region of the RYR1 protein where a significant number of previously reported pathogenic RYR1 missense mutations are found (PMID: 16084090). In summary, this variant has been reported in affected individuals and has been shown to alter protein function in vitro. However, there is conflicting evidence as to whether this variant segregates with disease. Finally, this variant is found in the population at an appreciable frequency which suggests it is not causative for disease. For these reasons, this change has been classified as a Variant of Uncertain Significance.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000259113 SCV000540243 uncertain significance not specified 2017-01-24 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant is present in ExAC at a MaxMAF of 0.24% in South Asian chromosomes (including 1 homozygote). It is present in 11 papers in HGMD, most of which classify the variant as a VUS as it has been seen in affected and unaffected patients. It is classified with 1 star in ClinVar as VUS by Emory and CSER and as Likely benign by Biesecker Lab. It is not present in the www.emhg.org RYR1 database.
Leiden Muscular Dystrophy (RYR1) RCV000119674 SCV000154581 not provided not provided no assertion provided not provided
PreventionGenetics RCV000119674 SCV000852739 uncertain significance not provided 2016-08-12 criteria provided, single submitter clinical testing

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