Submissions for variant NM_000540.3(RYR1):c.8342_8343del (p.Ile2781fs)

dbSNP: rs758580075

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
PreventionGenetics, part of Exact Sciences	RCV000721705	SCV000852833	pathogenic	not provided	2018-04-18	criteria provided, single submitter	clinical testing
GeneDx	RCV000721705	SCV001168610	pathogenic	not provided	2021-12-06	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; Observed in 5/23,590 (0.02%) alleles from individuals of African background, in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 21062345, 30611313, 27535533, 20839240, 30872186)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001209505	SCV001380942	pathogenic	RYR1-related disorder	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ile2781Argfs*49) 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 (rs758580075, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with autosomal recessive congenital myopathy (PMID: 20839240, 21062345). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 590611). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002507269	SCV002806695	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
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV002535011	SCV003761396	pathogenic	Congenital multicore myopathy with external ophthalmoplegia	2023-01-25	criteria provided, single submitter	curation	The heterozygous p.Ile2781ArgfsTer49 variant in RYR1 was identified by our study, in the compound heterozygous state with a variant of uncertain significance (ClinVar Variation ID: 845794), in one individual with minicore myopathy with external ophthalmoplegia. Trio exome analysis revealed that this variant was in trans with a variant of uncertain significance (ClinVar Variation ID: 845794). The p.Ile2781ArgfsTer49 variant in RYR1 has been previously reported in 5 unrelated individuals with minicore myopathy with external ophthalmoplegia (PMID: 30872186, PMID: 20839240, PMID: 20839240), but has been identified in 0.02% (9/41444) of African/African American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs758580075). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. Of these 5 unrelated individuals, 2 were compound heterozygotes who carried pathogenic variants in trans (PMID: 21062345, PMID: 20839240, ClinVar Variation ID: 132994) and 2 were compound heterozygotes who carried pathogenic variants with unknown phase (PMID: 20839240, ClinVar Variation ID: 132994), which increases the likelihood that the p.Ile2781ArgfsTer49 is pathogenic. This variant has also been reported in ClinVar (Variation ID: 590611) and has been interpreted as pathogenic by multiple submitters. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 2781 and leads to a premature termination codon 49 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the RYR1 gene is an established disease mechanism of autosomal recessive minicore myopathy with external ophthalmoplegia. In summary, this variant meets criteria to be classified as pathogenic for minicore myopathy with external ophthalmoplegia. ACMG/AMP Criteria applied: PVS1, PM3_Strong (Richards 2015).
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV002535011	SCV003807308	pathogenic	Congenital multicore myopathy with external ophthalmoplegia	2022-11-04	criteria provided, single submitter	clinical testing	ACMG classification criteria: PVS1 very strong, PM2 moderated, PM3 supporting, PP1 supporting
Revvity Omics, Revvity	RCV000721705	SCV003827293	pathogenic	not provided	2022-04-29	criteria provided, single submitter	clinical testing
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV001209505	SCV004046371	pathogenic	RYR1-related disorder		criteria provided, single submitter	clinical testing	This frameshifting variant in exon 53 of 106 introduces a premature stop codon and is therefore predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously reported as a compound heterozygous change in patients with congenital myopathy with central nuclei (PMID: 21062345, 30611313, 20839240). The c.8342_8343del (p.Ile2781ArgfsTer49) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.002% (5/280914) and is absent in the homozygous state, thus is presumed to be rare. Based on the available evidence, the c.8342_8343del (p.Ile2781ArgfsTer49) variant is classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV003514405	SCV004358151	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2023-03-30	criteria provided, single submitter	clinical testing	This variant deletes 2 nucleotides in exon 53 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. To our knowledge, this variant has not been reported in individuals affected with malignant hyperthermia susceptibility in the literature. This variant has been identified in 5/280914 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of RYR1 function due to haploinsufficiency is not an established disease mechanism for autosomal dominant malignant hyperthermia, although it is associated with other phenotype(s) (ClinVar Variation ID: 590611). Due to insufficient evidence, this variant is classified as a Variant of Uncertain Significance for autosomal dominant malignant hyperthermia.
Muscle and Diseases Team, Institut de Génétique et Biologie Moléculaire et Cellulaire	RCV004586901	SCV005038476	pathogenic	Centronuclear myopathy	2024-03-01	criteria provided, single submitter	research	PVS1+PM2+PM3_Supporting