ClinVar Miner

Submissions for variant NM_000540.3(RYR1):c.6796G>T (p.Gly2266Cys)

dbSNP: rs772803714
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001228966 SCV001401396 uncertain significance RYR1-Related Disorders 2022-07-25 criteria provided, single submitter clinical testing 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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 956206). This variant has not been reported in the literature in individuals affected with RYR1-related conditions. This variant is present in population databases (rs772803714, gnomAD 0.003%). This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 2266 of the RYR1 protein (p.Gly2266Cys). This variant also falls at the last nucleotide of exon 41, which is part of the consensus splice site for this exon.
GeneDx RCV002290647 SCV002578364 uncertain significance not provided 2022-08-11 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 32686686, 12668474)
Fulgent Genetics, Fulgent Genetics RCV002480752 SCV002794311 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 2021-08-27 criteria provided, single submitter clinical testing

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