ClinVar Miner

Submissions for variant NM_000540.3(RYR1):c.6274+1G>A

gnomAD frequency: 0.00004  dbSNP: rs1226228092
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000525713 SCV000659985 likely pathogenic RYR1-related disorder 2024-12-17 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 38 of the RYR1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or altered protein product. This variant is present in population databases (no rsID available, gnomAD 0.004%). Disruption of this splice site has been observed in individual(s) with clinical features of autosomal recessive RYR1-related conditions (PMID: 34528764). ClinVar contains an entry for this variant (Variation ID: 478250). Studies have shown that disruption of this splice site results in activation of a cryptic splice site, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 34528764). 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.
PreventionGenetics, part of Exact Sciences RCV000721603 SCV000852700 pathogenic not provided 2016-08-19 criteria provided, single submitter clinical testing
Eurofins Ntd Llc (ga) RCV000721603 SCV000857369 pathogenic not provided 2017-10-06 criteria provided, single submitter clinical testing
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego RCV000853333 SCV000996192 likely pathogenic Multiminicore myopathy 2018-08-28 criteria provided, single submitter clinical testing This variant affects the canonical splice donor site of intron 38 and is therefore predicted to interfere with splicing and result in loss of normal protein function. This variant has not been reported in the medical literature to our knowledge. It is present in the heterozygous state in the gnomAD population database at a frequency of 0.002% (5/265694) and thus is presumed to be rare. Based on the available evidence, the c.6274+1G>A variant is classified as likely pathogenic.
GeneDx RCV000721603 SCV001795380 pathogenic not provided 2023-02-08 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 (Shillington et al., 2021); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34528764)
Revvity Omics, Revvity RCV000721603 SCV002019914 pathogenic not provided 2019-07-23 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV004802184 SCV005425033 uncertain significance Malignant hyperthermia, susceptibility to, 1 2024-08-06 criteria provided, single submitter clinical testing This variant causes a G to A nucleotide substitution at the +1 position of intron 38 of the RYR1 gene. A RNA study on patient-derived RNA showed this variant alters splicing and is predicted to result in an absent or disrupted protein product. 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: 478250, PMID: 34528764). This variant has been identified in 6/270336 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.
Fulgent Genetics, Fulgent Genetics RCV005018959 SCV005647465 likely pathogenic Central core myopathy; Malignant hyperthermia, susceptibility to, 1; Congenital multicore myopathy with external ophthalmoplegia; King Denborough syndrome 2024-04-16 criteria provided, single submitter clinical testing

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