ClinVar Miner

Submissions for variant NM_000540.3(RYR1):c.3128G>A (p.Arg1043His)

gnomAD frequency: 0.00003  dbSNP: rs374776563
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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 RCV000559122 SCV000659913 uncertain significance RYR1-related disorder 2022-09-10 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1043 of the RYR1 protein (p.Arg1043His). This variant is present in population databases (rs374776563, gnomAD 0.008%). This missense change has been observed in individual(s) with a family history of malignant hyperthermia and atypical periodic paralysis and myalgia (PMID: 23558838, 29298851). ClinVar contains an entry for this variant (Variation ID: 478221). 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.
Fulgent Genetics, Fulgent Genetics RCV002483514 SCV002791804 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 2021-09-16 criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV003133372 SCV003814380 uncertain significance not provided 2019-04-22 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV003999497 SCV004820799 uncertain significance Malignant hyperthermia, susceptibility to, 1 2024-01-11 criteria provided, single submitter clinical testing This missense variant replaces arginine with histidine at codon 1043 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 been reported in an individual affected with malignant hyperthermia susceptibility (PMID: 23558838). This variant has been identified in 12/230810 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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