Submissions for variant NM_000540.3(RYR1):c.11590+1G>T

gnomAD frequency: 0.00001  dbSNP: rs113928116

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000438320	SCV000517043	pathogenic	not provided	2019-08-27	criteria provided, single submitter	clinical testing	Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Has not been previously published as pathogenic or benign to our knowledge
Invitae	RCV000803108	SCV000942967	likely pathogenic	RYR1-related disorder	2023-10-13	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 82 of the RYR1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in RYR1 are known to be pathogenic (PMID: 23919265, 25960145, 28818389, 30611313). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. Disruption of this splice site has been observed in individual(s) with autosomal recessive RYR1-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 379718). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002502495	SCV002811103	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	2021-07-26	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003996031	SCV004816502	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2023-05-04	criteria provided, single submitter	clinical testing	This variant causes a G to T nucleotide substitution at the +1 position of intron 82 of the RYR1 gene. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. This variant has not been reported in individuals affected with RYR1-related disorders in the literature. Loss of RYR1 function due to haploinsufficiency is not an established disease mechanism for autosomal dominant malignant hyperthermia susceptibility, although it has been associated with other phenotypes (ClinVar Variation ID: 379718). This variant has been identified in 3/247776 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV004017611	SCV004848432	likely pathogenic	Centronuclear myopathy	2020-08-11	criteria provided, single submitter	clinical testing	The c.11590+1G>T variant in RYR1 has not been previously reported in individuals with RYR1-related myopathies and has been identified in 0.003% (3/112590) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID 379718). This variant occurs within the canonical splice site (+/- 1,2) and is predicted to cause altered splicing leading to an abnormal or absent protein. Biallelic loss of function of the RYR1 gene is an established disease mechanism in autosomal recessive congenital fiber type disproportion (CFTD), multiminicore disease (MmD) and centronuclear myopathy (CNM) (Clarke 2010 PMID: 20583297, Amburgey 2013 PMID: 23919265). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive RYR1-related myopathies. ACMG/AMP Criteria applied: PVS1, PM2.