ClinVar Miner

Submissions for variant NM_000540.3(RYR1):c.4258C>T (p.Arg1420Cys)

gnomAD frequency: 0.00003  dbSNP: rs760625346
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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 RCV001981059 SCV002284300 uncertain significance RYR1-related disorder 2022-08-31 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1420 of the RYR1 protein (p.Arg1420Cys). This variant is present in population databases (rs760625346, gnomAD 0.01%). 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: 1492576). 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: "Probably Damaging"; Align-GVGD: "Class C0"). 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 RCV002492282 SCV002785895 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 2021-09-15 criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV003134330 SCV003813084 uncertain significance not provided 2023-08-02 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV004011087 SCV004840812 uncertain significance Malignant hyperthermia, susceptibility to, 1 2023-12-18 criteria provided, single submitter clinical testing This missense variant replaces arginine with cysteine at codon 1420 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 8/282346 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.
Ambry Genetics RCV004656819 SCV005161794 uncertain significance Inborn genetic diseases 2024-05-21 criteria provided, single submitter clinical testing The c.4258C>T (p.R1420C) alteration is located in exon 29 (coding exon 29) of the RYR1 gene. This alteration results from a C to T substitution at nucleotide position 4258, causing the arginine (R) at amino acid position 1420 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

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