ClinVar Miner

Submissions for variant NM_000540.2(RYR1):c.14524G>A (rs193922879)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CSER_CC_NCGL; University of Washington Medical Center RCV000148830 SCV000190570 uncertain significance Myopathy, congenital with cores 2014-06-01 no assertion criteria provided research
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000119524 SCV000701731 uncertain significance not provided 2017-08-15 criteria provided, single submitter clinical testing
Invitae RCV000546614 SCV000659852 uncertain significance RYR1-Related Disorders 2018-01-05 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 4842 of the RYR1 protein (p.Val4842Met). The valine residue is highly conserved and there is a small physicochemical difference between valine and methionine. This variant is present in population databases (rs193922879, ExAC 0.02%). This variant has been reported in the compound heterozygous state in multiple individuals affected with autosomal recessive congenital myopathy (PMID: 18253926, 21062345, 23394784, 20839240, 23553484, 23553787, 27854218) and an individual affected with malignant hyperthermia susceptibility (PMID: 21455645). However, in many of these individuals it was reported to co-occur in cis with an intronic variant, c.10348–6C>G, that has been determined to be pathogenic, which suggests that this c.14524G>A variant was not the primary cause of disease (PMID: 18253926, 21062345, 23394784, 20839240, 23553484). ClinVar contains an entry for this variant (Variation ID: 133075). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This missense change is located in the C-terminal of the RYR1 protein where a significant number of previously reported RYR1 missense mutations are found (PMID: 16084090). These observations suggest that a previously unreported missense substitution within this region may affect protein function, but experiments have not been done to test this possibility. 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000616859 SCV000711661 likely pathogenic Skeletal muscle disease 2015-10-08 criteria provided, single submitter clinical testing The p.Val4842Met variant in RYR1 has been reported in compound heterozygosity in 13 individuals with centronuclear myopathy (Monneri 2008, Wilmshurst 2010, Bevilacqua 2011). This variant segregated with disease in 3 affected relatives with centronuclear myopathy in 2 families. In the 13 individuals with centronuclear myopathy, the p.Val4842Met variant always occurred in conjunction with the c.10348-6C>G variant on the same copy of the gene (in cis). The p.Val4842Met variant has also been identified in 2/10334 of African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs193922879). Computational prediction tools and conservation analysis suggest that the p.Val4842Met 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, the p.Val4842Met variant is likely pathogenic for centronuclear myopathy in an autosomal recessive manner.
Leiden Muscular Dystrophy (RYR1) RCV000119524 SCV000154431 not provided not provided no assertion provided not provided
PreventionGenetics RCV000119524 SCV000852424 pathogenic not provided 2017-10-20 criteria provided, single submitter clinical testing

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