Submissions for variant NM_000540.3(RYR1):c.14173-2A>G

gnomAD frequency: 0.00002  dbSNP: rs1189024951

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000814221	SCV000954622	pathogenic	RYR1-related disorder	2024-12-18	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 97 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 (no rsID available, gnomAD 0.0009%). Disruption of this splice site has been observed in individuals with congenital myopathy (PMID: 22473935; internal data). ClinVar contains an entry for this variant (Variation ID: 590446). 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.
Revvity Omics, Revvity	RCV000721355	SCV002019112	likely pathogenic	not provided	2021-06-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000721355	SCV002599916	likely pathogenic	not provided	2022-10-31	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; Reported with two other variants in the RYR1 gene in a patient with congenital myopathy in the published literature; however, segregation information was not provided (Klein et al., 2012); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22473935)
Fulgent Genetics, Fulgent Genetics	RCV005004386	SCV002809835	likely pathogenic	Central core myopathy; Malignant hyperthermia, susceptibility to, 1; Congenital multicore myopathy with external ophthalmoplegia; King Denborough syndrome	2024-05-29	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003999821	SCV004815912	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2024-06-11	criteria provided, single submitter	clinical testing	This variant causes an A>G nucleotide substitution at the -2 position of intron 97 of the RYR1 gene. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. Loss of RYR1 function is not an established disease mechanism for autosomal dominant malignant hyperthermia, although it is associated with other phenotype(s) (ClinVar Variation ID: 590446). This variant has been identified in 1/251348 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.
PreventionGenetics, part of Exact Sciences	RCV000814221	SCV000852394	pathogenic	RYR1-related disorder	2023-10-28	no assertion criteria provided	clinical testing	The RYR1 c.14173-2A>G variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant has been reported to be causative for autosomal recessive RYR1-related congenital myopathy (Klein et al. 2012. PubMed ID: 22473935; also reported as patient 213 in Table S1, Amburgey et al. 2013. PubMed ID: 23919265). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-39068556-A-G). Variants that disrupt the consensus splice acceptor site in RYR1 are expected to be pathogenic. This variant is interpreted as pathogenic.