ClinVar Miner

Submissions for variant NM_000540.2(RYR1):c.10348-6C>G (rs193922837)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000119410 SCV000343561 pathogenic not provided 2017-08-15 criteria provided, single submitter clinical testing
Invitae RCV000535801 SCV000659748 pathogenic RYR1-Related Disorders 2019-06-05 criteria provided, single submitter clinical testing This sequence change falls in intron 68 of the RYR1 gene. It does not directly change the encoded amino acid sequence of the RYR1 protein. This variant is present in population databases (rs193922837, ExAC 0.02%). This variant has been reported in the compound heterozygous state with loss of function variants in multiple individuals affected with congenital myopathy (PMID: 18253926, 20839240, 21062345). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. This variant has also been reported to co-occur in cis with a missense change (p.Val4842Met). ClinVar contains an entry for this variant (Variation ID: 132994). Experimental studies have shown that this intronic change causes aberrant splicing of the RYR1 transcript and leads to a frameshift (PMID: 18253926). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000624604 SCV000741380 likely pathogenic Inborn genetic diseases 2016-03-31 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: UNCERTAIN: Alteration(s) of Uncertain Clinical Significance Detected
PreventionGenetics,PreventionGenetics RCV000119410 SCV000852208 pathogenic not provided 2015-09-15 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763427 SCV000894192 pathogenic Central core myopathy; Malignant hyperthermia, susceptibility to, 1; Minicore myopathy; Congenital myopathy with fiber type disproportion 2018-10-31 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000119410 SCV001246303 pathogenic not provided 2020-01-01 criteria provided, single submitter clinical testing
Leiden Muscular Dystrophy (RYR1) RCV000119410 SCV000154317 not provided not provided no assertion provided not provided
Broad Institute Rare Disease Group,Broad Institute RCV001249074 SCV001423025 pathogenic King Denborough syndrome 2020-01-29 no assertion criteria provided curation The c.10348-6C>G variant in RYR1 has been reported in at least 16 individuals of African descent in cis with p.Val4842Met (suggesting it is a founder variant in Africans) and 2 Chilean individuals with congenital myopathy, segregated with disease in 4 affected relatives from 2 families (PMID: 23553484, 20839240, 18253926, 21062345), and has been identified in 0.03204% (8/24966) of African chromosomes and 0.002822% (1/35438) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs193922837). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported pathogenic and likely pathogenic in ClinVar (Variation ID: 132994). In vitro functional studies provide some evidence that the c.10348-6C>G variant may slightly impact normal splicing and protein levels (PMID: 18253926, 21062345). However, these types of assays may not accurately represent biological function. Computational prediction tools, including splice predictors, and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. The presence of this variant in combination with loss of function variants and in at least 12 individuals with congenital myopathy increases the likelihood that the c.10348-6C>G variant is pathogenic (PMID: 23553484, 20839240, 18253926, 21062345). In summary, this variant meets criteria to be classified as pathogenic for congenital myopathy in an autosomal recessive manner based on multiple occurrences with loss of function variants in affected individuals and low prevalence in the general population. ACMG/AMP Criteria applied: PM3_VeryStrong, PM2, BP4, BP7, PP1, PS3_Supporting (Richards 2015).

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