ClinVar Miner

Submissions for variant NM_000540.3(RYR1):c.11321C>T (p.Ala3774Val)

gnomAD frequency: 0.00061  dbSNP: rs146361173
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia RCV000239317 SCV000296940 uncertain significance Malignant hypothermia 2015-09-24 criteria provided, single submitter clinical testing
GeneDx RCV000520252 SCV000618501 uncertain significance not provided 2022-12-01 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in a patient with central core disease who also harbored a second pathogenic RYR1 variant, phase unknown (Galleni et al., 2020).; This variant is associated with the following publications: (PMID: 33458582)
Invitae RCV000706929 SCV000836004 uncertain significance RYR1-related disorder 2022-10-05 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 3774 of the RYR1 protein (p.Ala3774Val). This variant is present in population databases (rs146361173, gnomAD 0.1%). This missense change has been observed in individual(s) with RYR1-related conditions (PMID: 33458582). ClinVar contains an entry for this variant (Variation ID: 252488). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on 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 RCV000520252 SCV000852247 uncertain significance not provided 2017-03-24 criteria provided, single submitter clinical testing
Athena Diagnostics RCV000520252 SCV001474668 uncertain significance not provided 2023-04-12 criteria provided, single submitter clinical testing Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is higher than would generally be expected for pathogenic variants in this gene (http://gnomad.broadinstitute.org). Computational tools predict that this variant is damaging.
Fulgent Genetics, Fulgent Genetics RCV002487106 SCV002777153 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 2021-08-03 criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV000520252 SCV003812448 uncertain significance not provided 2023-08-14 criteria provided, single submitter clinical testing

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