ClinVar Miner

Submissions for variant NM_000540.3(RYR1):c.4678G>A (p.Val1560Ile)

gnomAD frequency: 0.00002  dbSNP: rs767230160
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
PreventionGenetics, part of Exact Sciences RCV000721550 SCV000852636 uncertain significance not provided 2018-10-11 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV002493287 SCV002786012 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 2021-08-25 criteria provided, single submitter clinical testing
Invitae RCV002535008 SCV002989705 uncertain significance RYR1-related disorder 2022-07-26 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1560 of the RYR1 protein (p.Val1560Ile). This variant is present in population databases (rs767230160, 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: 590537). 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.
All of Us Research Program, National Institutes of Health RCV003999847 SCV004819758 uncertain significance Malignant hyperthermia, susceptibility to, 1 2024-01-11 criteria provided, single submitter clinical testing This missense variant replaces valine with isoleucine at codon 1560 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 8/282832 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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