Submissions for variant NM_000540.3(RYR1):c.10347+1G>A

dbSNP: rs111436401

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000210710	SCV000262855	likely pathogenic	Inborn genetic diseases	2013-09-13	criteria provided, single submitter	clinical testing
GeneDx	RCV000521927	SCV000618038	pathogenic	not provided	2022-05-26	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Previously reported in trans with another variant in multiple individuals with features of RYR1-related neuromuscular disease in the published literature and at GeneDx (Fattori et al., 2015; Farwell et al., 2015 Zecevic et al., 2020; Alkhunaizi et al.,2019); This variant is associated with the following publications: (PMID: 25356970, 31589614, 30652412, 25957634, 32655342)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000695241	SCV000823727	pathogenic	RYR1-related disorder	2024-08-05	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 68 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 (rs111436401, gnomAD 0.003%). Disruption of this splice site has been observed in individual(s) with autosomal recessive centronuclear myopathy (PMID: 25957634). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 224998). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
PreventionGenetics, part of Exact Sciences	RCV000521927	SCV000852207	pathogenic	not provided	2019-09-12	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000763426	SCV000894191	pathogenic	Central core myopathy; Malignant hyperthermia, susceptibility to, 1; Congenital multicore myopathy with external ophthalmoplegia; Congenital myopathy with fiber type disproportion	2018-10-31	criteria provided, single submitter	clinical testing
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000995628	SCV001149909	pathogenic	Congenital multicore myopathy with external ophthalmoplegia	2019-06-07	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000521927	SCV002019974	pathogenic	not provided	2021-04-12	criteria provided, single submitter	clinical testing
Laan Lab, Human Genetics Research Group, University of Tartu	RCV002259320	SCV002538618	pathogenic	Malignant hyperthermia, susceptibility to, 1	2021-05-01	criteria provided, single submitter	research
Fulgent Genetics, Fulgent Genetics	RCV005025343	SCV005647479	pathogenic	Central core myopathy; Malignant hyperthermia, susceptibility to, 1; Congenital multicore myopathy with external ophthalmoplegia; King Denborough syndrome	2024-06-15	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV002259320	SCV004827607	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2023-09-04	flagged submission	clinical testing	This variant causes a G to A nucleotide substitution at the +1 position of intron 68 of the RYR1 gene. Splice site prediction tools predict 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. To our knowledge, functional studies have not been reported for this variant. 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: 224998). Due to insufficient evidence, this variant is classified as a Variant of Uncertain Significance for autosomal dominant malignant hyperthermia.