Submissions for variant NM_000540.3(RYR1):c.6806dup (p.Ser2270fs)

dbSNP: rs886041380

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000266687	SCV000329915	pathogenic	not provided	2021-11-22	criteria provided, single submitter	clinical testing	Frameshift 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 (Lek et al., 2016); This variant is associated with the following publications: (PMID: 23919265, 22473935, 31589614)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001385846	SCV001585840	pathogenic	RYR1-related disorder	2023-09-05	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 280096). This premature translational stop signal has been observed in individual(s) with autosomal recessive RYR1-related myopathy (PMID: 22473935). This variant is present in population databases (no rsID available, gnomAD 0.007%). This sequence change creates a premature translational stop signal (p.Ser2270Leufs*13) 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).
Revvity Omics, Revvity	RCV000266687	SCV002019928	pathogenic	not provided	2021-09-09	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002503974	SCV002804750	pathogenic	Central core myopathy; Malignant hyperthermia, susceptibility to, 1; Congenital multicore myopathy with external ophthalmoplegia; Congenital myopathy with fiber type disproportion; King Denborough syndrome	2021-09-23	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV004546473	SCV005042687	pathogenic	Congenital multicore myopathy with external ophthalmoplegia		criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004804981	SCV005425063	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2024-07-20	criteria provided, single submitter	clinical testing	This variant inserts 1 nucleotide in exon 42 of the RYR1 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. Loss of RYR1 function due to truncation variants is not an established disease mechanism for autosomal dominant malignant hyperthermia, although it is associated with other phenotype(s) (ClinVar variation ID: 280096). This variant has been identified in 1/31368 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.