ClinVar Miner

Submissions for variant NM_001042723.2(RYR1):c.12845_12854delinsT (p.Ala4282_Ala4285delinsVal) (rs796065337)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000721293 SCV000233221 uncertain significance not provided 2014-07-11 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000302834 SCV000412899 uncertain significance Neuromuscular disease, congenital, with uniform type 1 fiber 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000357672 SCV000412900 uncertain significance Malignant hyperthermia susceptibility 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000406984 SCV000412901 uncertain significance Central core myopathy 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000304831 SCV000412902 uncertain significance Multiminicore Disease 2016-06-14 criteria provided, single submitter clinical testing
GeneDx RCV000721293 SCV000582936 uncertain significance not provided 2018-11-06 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the RYR1 gene. The c.12860_12869del10insT variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. No data are available from control populations to assess the frequency of this variant. The c.12860_12869del10insT variant results in an in-frame deletion of 4 amino acid residues and the insertion of a single Valine residue, denoted p.Ala4287_Ala4290delinsV. The c.12860_12869del10insT variant alters residues that are not conserved across species, and in silico analysis predicts this variant likely does not alter the protein structure/function. However, other in-frame variants in the RYR1 gene have been reported in the Human Gene Mutation Database in association with RYR1-related disorders (Stenson et al., 2014). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000540221 SCV000659797 uncertain significance RYR1-Related Disorders 2016-10-08 criteria provided, single submitter clinical testing This sequence change deletes 10 nucleotides and inserts 1 nucleotide into exon 91 of the RYR1 mRNA (c.12860_12869delinsT). This leads to the deletion of amino acids 4287-4290 and the insertion of 1 amino acid (valine) in the RYR1 protein (p.Ala4287_Ala4290delinsVal), but otherwise preserves the integrity of the reading frame. While this variant is present in population databases, the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in an individual with a RYR1-related disease. ClinVar contains an entry for this variant (Variation ID: 199216). Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the deleted and inserted amino acids is currently unknown. This missense change is located in the C-terminal mutational hotspot of the RYR1 protein where a significant number of previously reported RYR1 missense mutations are found (PMID: 16084090). In summary, this is a rare variant with uncertain impact on protein function. There is no indication that this variant causes disease, but the evidence is insufficient at this time to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
PreventionGenetics,PreventionGenetics RCV000721293 SCV000852317 uncertain significance not provided 2016-05-24 criteria provided, single submitter clinical testing

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