ClinVar Miner

Submissions for variant NM_000540.3(RYR1):c.7781C>T (p.Ser2594Leu)

gnomAD frequency: 0.00003  dbSNP: rs749564145
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
PreventionGenetics, part of Exact Sciences RCV000721665 SCV000852792 uncertain significance not provided 2018-01-09 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001061704 SCV001226456 uncertain significance RYR1-related disorder 2022-08-16 criteria provided, single submitter clinical testing This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 2594 of the RYR1 protein (p.Ser2594Leu). This variant is present in population databases (rs749564145, gnomAD 0.007%). 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: 590595). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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 RCV002499331 SCV002816836 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 2021-09-30 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000721665 SCV004141613 uncertain significance not provided 2022-04-01 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV003999861 SCV004820927 uncertain significance Malignant hyperthermia, susceptibility to, 1 2023-11-30 criteria provided, single submitter clinical testing This missense variant replaces serine with leucine at codon 2594 of the RYR1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 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 6/249496 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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