ClinVar Miner

Submissions for variant NM_000540.3(RYR1):c.2681C>T (p.Pro894Leu)

gnomAD frequency: 0.00007  dbSNP: rs758631999
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000694850 SCV000823312 uncertain significance RYR1-related disorder 2022-03-11 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 894 of the RYR1 protein (p.Pro894Leu). This variant is present in population databases (rs758631999, gnomAD 0.01%). 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: 573233). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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, part of Exact Sciences RCV000721469 SCV000852539 uncertain significance not provided 2016-05-20 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV002507208 SCV002815402 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 2021-11-15 criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV000721469 SCV003814424 uncertain significance not provided 2022-03-15 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000721469 SCV004703413 uncertain significance not provided 2024-06-01 criteria provided, single submitter clinical testing RYR1: PM2
All of Us Research Program, National Institutes of Health RCV003999627 SCV004821032 uncertain significance Malignant hyperthermia, susceptibility to, 1 2024-02-05 criteria provided, single submitter clinical testing This missense variant replaces proline with leucine at codon 894 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 been identified in 7/277200 chromosomes 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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