ClinVar Miner

Submissions for variant NM_000540.3(RYR1):c.14563G>T (p.Val4855Leu)

gnomAD frequency: 0.00005  dbSNP: rs528225943
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001302549 SCV001491763 uncertain significance RYR1-related disorder 2023-07-14 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 4855 of the RYR1 protein (p.Val4855Leu). This variant is present in population databases (rs528225943, gnomAD 0.02%). 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: 1005641). 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.
GeneDx RCV001732118 SCV001983135 uncertain significance not provided 2020-10-16 criteria provided, single submitter clinical testing Has not been previously published as pathogenic or benign to our knowledge; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect
Fulgent Genetics, Fulgent Genetics RCV002486164 SCV002791903 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 2021-10-12 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV004005012 SCV004820470 uncertain significance Malignant hyperthermia, susceptibility to, 1 2023-10-27 criteria provided, single submitter clinical testing This missense variant replaces valine with leucine at codon 4855 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 not been reported in individuals affected with RYR1-related disorders in the literature. This variant has been identified in 4/282854 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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