ClinVar Miner

Submissions for variant NM_000540.2(RYR1):c.10347+1G>A (rs111436401)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000210710 SCV000262855 likely pathogenic Inborn genetic diseases 2013-09-13 criteria provided, single submitter clinical testing
GeneDx RCV000521927 SCV000618038 pathogenic not provided 2017-09-08 criteria provided, single submitter clinical testing The c.10347+1G>A variant in the RYR1 gene has been reported previously in an individual with centronuclear myopathy and in an individual with minicore myopathy, both who were compound heterozygous for the c.10347+1G>A variant and another variant (Fattori et al., 2015; Farwell et al., 2015). This splice site variant destroys the canonical splice donor site in intron 68. It is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. The c.10347+1G>A variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). We interpret c.10347+1G>A as a pathogenic variant.
Invitae RCV000695241 SCV000823727 pathogenic RYR1-Related Disorders 2019-03-05 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 68 of the RYR1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been observed on the opposite chromosome (in trans) from a likely pathogenic variant in an individual affected with centronuclear myopathy (PMID: 25957634). ClinVar contains an entry for this variant (Variation ID: 224998). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in RYR1 are known to be pathogenic (PMID: 20583297, 23919265). For these reasons, this variant has been classified as Pathogenic.
PreventionGenetics,PreventionGenetics RCV000521927 SCV000852207 likely pathogenic not provided 2016-05-03 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763426 SCV000894191 pathogenic Central core myopathy; Malignant hyperthermia, susceptibility to, 1; Minicore myopathy; Congenital myopathy with fiber type disproportion 2018-10-31 criteria provided, single submitter clinical testing
Institute of Human Genetics,Klinikum rechts der Isar RCV000995628 SCV001149909 pathogenic Minicore myopathy 2019-06-07 criteria provided, single submitter clinical testing

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