ClinVar Miner

Submissions for variant NM_000540.3(RYR1):c.4766A>C (p.Gln1589Pro)

gnomAD frequency: 0.00001  dbSNP: rs780420237
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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 RCV000655499 SCV000777430 uncertain significance RYR1-related disorder 2022-07-24 criteria provided, single submitter clinical testing This sequence change replaces glutamine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 1589 of the RYR1 protein (p.Gln1589Pro). This variant is present in population databases (rs780420237, gnomAD 0.002%). This missense change has been observed in individual(s) with clinical features of RYR1-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 544377). 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 expected to disrupt RYR1 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 RCV000721555 SCV000852643 uncertain significance not provided 2016-08-26 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV002477466 SCV002779118 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 2021-09-10 criteria provided, single submitter clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV002534229 SCV003761230 uncertain significance RYR1-related myopathy 2023-01-25 criteria provided, single submitter curation The heterozygous p.Gln1589Pro variant in RYR1 was identified by our study, in the compound heterozygous state with a variant of uncertain significance (NC_000019.10:g.38587339G>T), in one individual with central core disease. Familial segregation analysis revealed that this variant was in trans with another variant of uncertain significance (NC_000019.10:g.38587339G>T). The p.Gln1589Pro variant in RYR1 has not been previously reported in the literature in individuals with RYR1-related myopathy but has been identified in 0.001% (1/68664) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs780420237). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID: 544377) and has been interpreted as a variant of uncertain significance by Invitae and Prevention Genetics. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Gln1589Pro variant is uncertain. ACMG/AMP Criteria applied: PM2_Supporting, PP3 (Richards 2015).
All of Us Research Program, National Institutes of Health RCV004807073 SCV005431009 uncertain significance Malignant hyperthermia, susceptibility to, 1 2024-05-14 criteria provided, single submitter clinical testing This missense variant replaces glutamine with proline at codon 1589 of the RYR1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. 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 1/169454 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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