ClinVar Miner

Submissions for variant NM_000540.3(RYR1):c.6797-6_6798del

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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 RCV002907848 SCV003244865 pathogenic RYR1-related disorder 2023-08-04 criteria provided, single submitter clinical testing This variant has been observed in individual(s) with autosomal recessive centronuclear myopathy (PMID: 28818389). 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. This variant is present in population databases (no rsID available, gnomAD 0.003%). This variant results in the deletion of part of exon 42 (c.6797-6_6798del) 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). ClinVar contains an entry for this variant (Variation ID: 2039302). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site.
Muscle and Diseases Team, Institut de Génétique et Biologie Moléculaire et Cellulaire RCV004587384 SCV005038485 pathogenic Centronuclear myopathy 2024-03-01 criteria provided, single submitter research PVS1+PM2+PP1
Clinical Genetics Laboratory, Exon Genomics RCV004546751 SCV005043064 pathogenic Congenital multicore myopathy with external ophthalmoplegia 2024-05-07 criteria provided, single submitter clinical testing Null variant (intronic within ±2 of splice site) in gene RYR1. Loss-of-function is a known mechanism of disease (gene has 372 reported pathogenic LOF variants). ClinVar classifies this variant as Pathogenic, 1 star (reviewed Feb '23, 1 submission of which 1 is from high confidence submitter), citing 5 articles (28818389, 23919265, 20839240, 20583297 and 16199547). Variant not found in gnomAD genomes, good gnomAD genomes coverage = 31.5.

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