ClinVar Miner

Submissions for variant NM_000540.3(RYR1):c.9772G>A (p.Glu3258Lys)

gnomAD frequency: 0.00006  dbSNP: rs754431075
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000688302 SCV000815907 uncertain significance RYR1-related disorder 2024-01-25 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 3258 of the RYR1 protein (p.Glu3258Lys). This variant is present in population databases (rs754431075, gnomAD 0.04%). 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: 568062). 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 RCV001549837 SCV001770065 uncertain significance not provided 2019-12-05 criteria provided, single submitter clinical testing In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge
Molecular Genetics, Royal Melbourne Hospital RCV002221249 SCV002498659 uncertain significance RYR1-related myopathy 2023-03-30 criteria provided, single submitter clinical testing This sequence change in RYR1 is predicted to replace glutamic acid with lysine at codon 3258, p.(Glu3258Lys). The glutamic acid residue is highly conserved (100 vertebrates, UCSC), and is located in exon 66 outside of the C-terminal region, amino acids 4631-4991, that is defined as a mutational hotspot. There is a small physicochemical difference between glutamic acid and lysine. The highest population minor allele frequency in gnomAD v2.1 is 0.03% (12/3,4584 alleles, 0 homozygotes) in the Latino/admixed American population. The variant has been reported as a variant of uncertain significance (ClinVar ID: 568062), and to our knowledge, has not been reported in the literature in any individuals with RYR1-related disorders. Multiple lines of computational evidence predict a deleterious effect for the missense substitution (5/5 algorithms). Based on the classification scheme RMH Modified ACMG Guidelines v1.4.0, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: PP3.
Fulgent Genetics, Fulgent Genetics RCV002477538 SCV002775423 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 2021-09-01 criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV001549837 SCV004236631 uncertain significance not provided 2023-06-28 criteria provided, single submitter clinical testing

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