ClinVar Miner

Submissions for variant NM_000540.3(RYR1):c.2897C>T (p.Pro966Leu)

gnomAD frequency: 0.00001  dbSNP: rs143179371
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001048927 SCV001212957 likely pathogenic RYR1-related disorder 2024-11-29 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 966 of the RYR1 protein (p.Pro966Leu). This variant is present in population databases (rs143179371, gnomAD 0.009%). This missense change has been observed in individuals with autosomal recessive myopathy and/or clinical features of RYR1-related conditions (PMID: 28357410, 31127727, 32528171; internal data). ClinVar contains an entry for this variant (Variation ID: 845794). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt RYR1 protein function with a positive predictive value of 95%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Fulgent Genetics, Fulgent Genetics RCV002489605 SCV002789505 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 2021-08-19 criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV003130122 SCV003815008 uncertain significance not provided 2021-05-12 criteria provided, single submitter clinical testing
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre RCV003989632 SCV004808011 uncertain significance Central core myopathy 2024-03-29 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV004004791 SCV004825350 uncertain significance Malignant hyperthermia, susceptibility to, 1 2024-07-29 criteria provided, single submitter clinical testing This missense variant replaces proline with leucine at codon 966 of the RYR1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with autosomal dominant malignant hyperthermia susceptibility, although it has been reported in individuals affected with myopathy (PMID: 28357410, 31127727). 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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