Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ce |
RCV001531894 | SCV001747215 | likely pathogenic | not provided | 2021-06-01 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV003757223 | SCV004531954 | pathogenic | RYR1-related disorder | 2023-10-14 | criteria provided, single submitter | clinical testing | This sequence change affects a donor splice site in intron 99 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 not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with autosomal recessive arthrogryposis multiplex congenita (PMID: 24319099). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1176378). 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. |
| Laboratory for Molecular Medicine, |
RCV004017845 | SCV004848759 | likely pathogenic | Central core myopathy | 2022-08-26 | criteria provided, single submitter | clinical testing | The c.14364+1G>A variant in RYR1 has been reported in one individual with arthrogryposis multiplex congenita (AMC) as a compound heterozygous with a pathogenic variant (Laque´rriere 2014 PMID: 24319099), and was absent in large population databases. AMC may occur due to an underlying myopathy consistent with RYR1-related myopathies. 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, this variant meets criteria to be classified as pathogenic for autosomal recessive RYR1-related myopathies. ACMG/AMP Criteria applied: PVS1, PM3,PM2_Supporting. |
| All of Us Research Program, |
RCV004804225 | SCV005426520 | uncertain significance | Malignant hyperthermia, susceptibility to, 1 | 2024-03-28 | criteria provided, single submitter | clinical testing |