ClinVar Miner

Submissions for variant NM_000540.3(RYR1):c.13565C>A (p.Pro4522His)

dbSNP: rs145167688
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Neuberg Centre For Genomic Medicine, NCGM RCV001823664 SCV002073269 uncertain significance Central core myopathy criteria provided, single submitter clinical testing The missense variant p.P4522H in RYR1 (NM_000540.3) has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.P4522H variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. There is a moderate physicochemical difference between proline and histidine. The p.P4522H missense variant is predicted to be damaging by both SIFT and PolyPhen2. The nucleotide c.13565 in RYR1 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance.
Fulgent Genetics, Fulgent Genetics RCV002478069 SCV002777243 uncertain significance Central core myopathy; Malignant hyperthermia, susceptibility to, 1; Congenital multicore myopathy with external ophthalmoplegia; Congenital myopathy with fiber type disproportion; King Denborough syndrome 2021-08-02 criteria provided, single submitter clinical testing
Invitae RCV003757229 SCV004528858 uncertain significance RYR1-related disorder 2023-12-11 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with histidine, which is basic and polar, at codon 4522 of the RYR1 protein (p.Pro4522His). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with RYR1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1339210). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt RYR1 protein function with a negative predictive value of 95%. 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.
All of Us Research Program, National Institutes of Health RCV004009164 SCV004829703 uncertain significance Malignant hyperthermia, susceptibility to, 1 2023-08-08 criteria provided, single submitter clinical testing This missense variant replaces proline with histidine at codon 4522 of the RYR1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with RYR1-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

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