Submissions for variant NM_000540.3(RYR1):c.9847C>T (p.Arg3283Ter)

gnomAD frequency: 0.00003  dbSNP: rs752199191

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000627253	SCV000748245	pathogenic	not provided	2023-11-08	criteria provided, single submitter	clinical testing	Identified in two siblings with multiminicore disease who were also found to harbor a second RYR1 variant and testing of one parent suggests the variants are likely present on opposite alleles (in trans) (PMID: 23919265); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 33146414, 23919265)
PreventionGenetics, part of Exact Sciences	RCV000627253	SCV000852894	pathogenic	not provided	2015-09-01	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000627253	SCV002019967	pathogenic	not provided	2019-08-14	criteria provided, single submitter	clinical testing
Centogene AG - the Rare Disease Company	RCV001809708	SCV002059227	pathogenic	Congenital multicore myopathy with external ophthalmoplegia	2021-11-11	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001855333	SCV002243615	pathogenic	RYR1-related disorder	2023-11-15	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg3283*) in the RYR1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RYR1 are known to be pathogenic (PMID: 23919265, 25960145, 28818389, 30611313). This variant is present in population databases (rs752199191, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with autosomal recessive multiminicore disease (PMID: 23919265). ClinVar contains an entry for this variant (Variation ID: 523793). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002499018	SCV002813239	pathogenic	Central core myopathy; Malignant hyperthermia, susceptibility to, 1; Congenital multicore myopathy with external ophthalmoplegia; Congenital myopathy with fiber type disproportion; King Denborough syndrome	2022-02-07	criteria provided, single submitter	clinical testing
Lifecell International Pvt. Ltd	RCV001809708	SCV003852755	pathogenic	Congenital multicore myopathy with external ophthalmoplegia		criteria provided, single submitter	clinical testing	A Heterozygous Nonsense variant c.9847C>T in Exon 66 of the RYR1 gene that results in the amino acid substitution p.Arg3283* was identified. The observed variant has a minor allele frequency of 0.00003% in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score. Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic (Variation ID: 523793). The variant has been previously reported by Clarke NF, et al., 2010. This sequence change creates a premature translational stop signal (p.Arg3283*) in the RYR1 gene and result in an absent or disrupted protein product. Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines.
Athena Diagnostics	RCV000627253	SCV004229932	likely pathogenic	not provided	2023-05-24	criteria provided, single submitter	clinical testing	This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant appears to segregate with autosomal recessive RYR1-related myopathy in at least one family.