ClinVar Miner

Submissions for variant NM_000540.3(RYR1):c.6838G>T (p.Val2280Phe)

gnomAD frequency: 0.00003  dbSNP: rs193922797
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000658391 SCV000780163 uncertain significance not provided 2018-05-29 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the RYR1 gene. The V2280F variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The V2280F variant is observed in 1/8730 (0.01%) alleles from individuals of African backgroun in large population cohorts (Lek et al., 2016). The V2280F variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Fulgent Genetics, Fulgent Genetics RCV000765448 SCV000896739 uncertain significance Central core myopathy; Malignant hyperthermia, susceptibility to, 1; Congenital multicore myopathy with external ophthalmoplegia; Congenital myopathy with fiber type disproportion 2018-10-31 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV004004190 SCV004832765 uncertain significance Malignant hyperthermia, susceptibility to, 1 2023-06-26 criteria provided, single submitter clinical testing This missense variant replaces valine with phenylalanine at codon 2280 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 1/31380 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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