ClinVar Miner

Submissions for variant NM_000540.3(RYR1):c.424+4C>A

gnomAD frequency: 0.00002  dbSNP: rs772775579
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000697906 SCV000826540 uncertain significance RYR1-related disorder 2022-08-16 criteria provided, single submitter clinical testing This sequence change falls in intron 5 of the RYR1 gene. It does not directly change the encoded amino acid sequence of the RYR1 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs772775579, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with RYR1-related conditions. ClinVar contains an entry for this variant (Variation ID: 575635). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Fulgent Genetics, Fulgent Genetics RCV002477589 SCV002801398 uncertain significance Central core myopathy; Malignant hyperthermia, susceptibility to, 1; Congenital multicore myopathy with external ophthalmoplegia; Congenital myopathy with fiber type disproportion; King Denborough syndrome 2022-02-10 criteria provided, single submitter clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV003225953 SCV003922340 uncertain significance RYR1-related myopathy 2023-05-02 criteria provided, single submitter curation The heterozygous c.424+4C>A variant in RYR1 was identified by our study, in the compound heterozygous state with a likely pathogenic variant (ClinVar Variation ID: 65996), in two siblings with congenital myopathy and ophthalmoplegia. Familial exome analysis revealed that this variant was in trans with a likely pathogenic variant (ClinVar Variation ID: 65996). The c.424+4C>A variant in RYR1 has not been previously reported in individuals with RYR1-related myopathy but has been identified in 0.004% (3/68006) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs772775579). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID: 575635) and has been interpreted as a variant of uncertain significance by Invitae. This variant is located in the 5' splice region. Computational tools do not suggest an impact to splicing. However, this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of the c.424+4C>A variant is uncertain. ACMG/AMP Criteria applied: PM2_Supporting, PM3, BP4 (Richards 2015).

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