Submissions for variant NM_000540.3(RYR1):c.5340_5341del (p.Cys1781fs)

gnomAD frequency: 0.00004  dbSNP: rs779723153

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000480365	SCV000572217	pathogenic	not provided	2024-08-17	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 (gnomAD); Has not been previously published as pathogenic or benign to our knowledge
CeGaT Center for Human Genetics Tuebingen	RCV000480365	SCV001151847	likely pathogenic	not provided	2019-04-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001204775	SCV001375996	pathogenic	RYR1-related disorder	2023-07-07	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 422691). This variant is present in population databases (rs779723153, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with RYR1-related conditions. For these reasons, this variant has been classified as Pathogenic. This sequence change creates a premature translational stop signal (p.Cys1781Phefs*76) 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).
Fulgent Genetics, Fulgent Genetics	RCV002506175	SCV002815627	likely pathogenic	Central core myopathy; Malignant hyperthermia, susceptibility to, 1; Congenital multicore myopathy with external ophthalmoplegia; Congenital myopathy with fiber type disproportion; King Denborough syndrome	2021-09-09	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000480365	SCV003827282	pathogenic	not provided	2022-04-21	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004003385	SCV004820855	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2024-05-30	criteria provided, single submitter	clinical testing	This variant deletes 2 nucleotides in exon 34 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. This variant has not been reported in individuals affected with autosomal dominant malignant hyperthermia susceptibility in the literature, although it is associated with other phenotype(s) (ClinVar variation ID: 422691). This variant has been identified in 3/276212 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of RYR1 function due to truncation variants is not an established disease mechanism for autosomal dominant malignant hyperthermia susceptibility. Due to insufficient evidence, this variant is classified as a Variant of Uncertain Significance for malignant hyperthermia susceptibility.