ClinVar Miner

Submissions for variant NM_000540.3(RYR1):c.7336G>A (p.Gly2446Ser)

gnomAD frequency: 0.00006  dbSNP: rs375148516
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000655527 SCV000777458 uncertain significance RYR1-related disorder 2022-06-13 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 2446 of the RYR1 protein (p.Gly2446Ser). This variant is present in population databases (rs375148516, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of periodic paralyisis (PMID: 29298851). ClinVar contains an entry for this variant (Variation ID: 544400). 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.
GeneDx RCV002222583 SCV002499838 uncertain significance not provided 2022-04-06 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in a patient with intermittent limb weakness with a second RYR1 variant (Matthews et al., 2018); This variant is associated with the following publications: (PMID: 12668474, 29298851)
MGZ Medical Genetics Center RCV002289944 SCV002579702 uncertain significance Central core myopathy 2022-05-10 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV002507138 SCV002814559 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
CeGaT Center for Human Genetics Tuebingen RCV002222583 SCV004702192 uncertain significance not provided 2024-02-01 criteria provided, single submitter clinical testing RYR1: PM1, PM2, PP3
All of Us Research Program, National Institutes of Health RCV004004140 SCV004820912 uncertain significance Malignant hyperthermia, susceptibility to, 1 2023-12-01 criteria provided, single submitter clinical testing This missense variant replaces glycine with serine at codon 2446 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 autosomal dominant malignant hyperthermia in the literature, although it has been reported in other phenotype(s) (ClinVar variation ID: 544400; PMID: 29298851). This variant has been identified in 13/282372 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Due to insufficient evidence, this variant is classified as a Variant of Uncertain Significance for autosomal dominant malignant hyperthermia.

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