ClinVar Miner

Submissions for variant NM_000540.3(RYR1):c.7699C>T (p.Pro2567Ser)

gnomAD frequency: 0.00005  dbSNP: rs374982449
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000655517 SCV000777448 uncertain significance RYR1-related disorder 2021-09-01 criteria provided, single submitter clinical testing This sequence change replaces proline with serine at codon 2567 of the RYR1 protein (p.Pro2567Ser). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and serine. This variant is present in population databases (rs374982449, ExAC 0.005%). This missense change has been observed in individual(s) with clinical features of RYR1-related conditions (PMID: 31994743). ClinVar contains an entry for this variant (Variation ID: 544392). 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. 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.
GeneDx RCV002254939 SCV002526321 uncertain significance not provided 2022-05-24 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported previously as a paternally inherited variant of uncertain significance in a fetus with pleural effusions, scalp edema, and growth restriction (Jelin et al., 2020); This variant is associated with the following publications: (PMID: 31994743)
Fulgent Genetics, Fulgent Genetics RCV002493063 SCV002797664 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 2021-09-01 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV004004135 SCV004820921 uncertain significance Malignant hyperthermia, susceptibility to, 1 2024-01-03 criteria provided, single submitter clinical testing This missense variant replaces proline with serine at codon 2567 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 autosomal dominant malignant hyperthermia in the literature, although it has been reported in other phenotype(s) (PMID: 31994743). This variant has been identified in 12/281522 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Due to insufficient evidence, this variant is classified as a Variant of Uncertain Significance for autosomal dominant malignant hyperthermia.

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