ClinVar Miner

Submissions for variant NM_000540.2(RYR1):c.12884C>T (p.Ala4295Val) (rs193922855)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory, University of Chicago RCV000119469 SCV000194800 uncertain significance not provided 2014-05-14 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000119469 SCV000233217 uncertain significance not provided 2015-05-26 criteria provided, single submitter clinical testing
GeneDx RCV000119469 SCV000234956 uncertain significance not provided 2018-10-16 criteria provided, single submitter clinical testing The A4295V variant in the RYR1 gene has been reported in multiple individuals with RYR1-related clinical features including multminicore disease, malignant hyperthermia susceptibility, central core disease, episodes of rhabdomyolysis, and exertional heat illness; however, each of these individuals harbored additional variants in the RYR1 gene. (Jeong et al., 2008; Klein et al., 2012; Dlamini et al., 2013; Fiszer et al., 2015). Additionally, A4295V was noted to be inherited from the asymptomatic parents of two of these reported patients (Klein et al., 2012). This variant is observed in 41/25,072 alleles (0.16%) in large population cohorts, and in 112/87,770 (0.13%) alleles from unaffected relatives of individuals undergoing testing at GeneDx (Lek et al., 2016). The A4295V 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 that this variant does not alter protein structure/function. We interpret A4295V as a variant of uncertain significance.
Invitae RCV000529209 SCV000659802 uncertain significance RYR1-Related Disorders 2018-12-28 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 4295 of the RYR1 protein (p.Ala4295Val). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and valine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This variant has been reported in two families affected with malignant hyperthermia susceptibility (MHS) (PMID: 19513315, 21157159). However, a pathogenic RYR1 variant (p.Arg2435His) present on the same allele (in cis) was identified in these families, which suggests that this c.12884C>T substitution in RYR1 may not be the primary cause of disease in the families. This variant has also been reported in an individual affected with exertional heat illness (EHI) who tested MHS normal by an in vitro contracture test and in an individual affected with congenital fiber type disproportion (PMID: 25658027, 29382405). In addition, this variant has been reported in two individuals affected with myopathy, but was also identified in their unaffected parents (PMID: 22473935). ClinVar contains an entry for this variant (Variation ID: 133043). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. This missense change is located in a region 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.
PreventionGenetics,PreventionGenetics RCV000119469 SCV000852324 uncertain significance not provided 2018-02-19 criteria provided, single submitter clinical testing
Leiden Muscular Dystrophy (RYR1) RCV000119469 SCV000154376 not provided not provided no assertion provided not provided

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