Submissions for variant NM_000540.3(RYR1):c.9472+1G>A

gnomAD frequency: 0.00001  dbSNP: rs776697656

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000522844	SCV000620011	likely pathogenic	not provided	2017-08-18	criteria provided, single submitter	clinical testing	The c.9472+1 G>A variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. This variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The c.9472+1 G>A splice site variant destroys the canonical splice donor site for intron 63. It is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. However, in the absence of RNA/functional studies the actual effect of this sequence change in this individual is unknown.
Ambry Genetics	RCV001266974	SCV001445155	likely pathogenic	Inborn genetic diseases	2018-02-06	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000522844	SCV002019106	likely pathogenic	not provided	2023-07-21	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001858000	SCV002266738	likely pathogenic	RYR1-related disorder	2023-10-14	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 63 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). This variant is present in population databases (rs776697656, gnomAD 0.006%). Disruption of this splice site has been observed in individual(s) with hydrops fetalis (PMID: 34625927). ClinVar contains an entry for this variant (Variation ID: 451330). 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	RCV002506276	SCV002810901	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	2021-12-27	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004003622	SCV004834874	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2023-10-06	criteria provided, single submitter	clinical testing	This pathogenicity assessment is for autosomal dominant malignant hyperthermia susceptibility phenotype. This canonical splice site variant is predicted to result in an absent RYR1 protein product. Loss of RYR1 function due to haploinsufficiency is associated with congenital myopathy (https://clinicalgenome.org/), but it is not an established disease mechanism for autosomal dominant malignant hyperthermia susceptibility. Therefore, this variant is classified as a Variant of Uncertain Significance for malignant hyperthermia susceptibility.