ClinVar Miner

Submissions for variant NM_000540.3(RYR1):c.5607G>C (p.Glu1869Asp)

gnomAD frequency: 0.00001  dbSNP: rs1043076830
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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 RCV001954629 SCV002195978 uncertain significance RYR1-related disorder 2023-12-02 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 1869 of the RYR1 protein (p.Glu1869Asp). This variant is present in population databases (no rsID available, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with RYR1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1419196). 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 with a negative predictive value of 95%. 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 RCV002484536 SCV002791163 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 2021-10-04 criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV003130606 SCV003813075 uncertain significance not provided 2019-07-01 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV004010888 SCV004832445 uncertain significance Malignant hyperthermia, susceptibility to, 1 2024-01-11 criteria provided, single submitter clinical testing This missense variant replaces glutamic acid with aspartic acid at codon 1869 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 RYR1-related disorders in the literature. This variant has been identified in 3/280198 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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