Submissions for variant NM_000540.3(RYR1):c.10348-6C>G

gnomAD frequency: 0.00010  dbSNP: rs193922837

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000119410	SCV000343561	pathogenic	not provided	2017-08-15	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000535801	SCV000659748	pathogenic	RYR1-related disorder	2024-01-11	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. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs193922837, gnomAD 0.03%). This variant has been observed in individual(s) with congenital myopathy (PMID: 18253926, 20839240, 21062345). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 132994). Studies have shown that this variant results in retention of intron 68 and introduces a premature termination codon (PMID: 18253926). The resulting mRNA is expected to undergo nonsense-mediated decay. 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
PreventionGenetics, part of Exact Sciences	RCV000119410	SCV000852208	pathogenic	not provided	2015-09-15	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002477304	SCV000894192	pathogenic	Central core myopathy; Malignant hyperthermia, susceptibility to, 1; Congenital multicore myopathy with external ophthalmoplegia; Congenital myopathy with fiber type disproportion; King Denborough syndrome	2021-09-27	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000119410	SCV001246303	pathogenic	not provided	2020-01-01	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001249074	SCV001423025	pathogenic	King Denborough syndrome	2020-01-29	criteria provided, single submitter	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).
GeneDx	RCV000119410	SCV001873700	pathogenic	not provided	2022-11-09	criteria provided, single submitter	clinical testing	Reported previously in multiple unrelated individuals with congenital myopathy who also harbored at least one additional RYR1 variant, although phase is not always known (Monnier et al., 2008; Wilmshurst et al., 2010; Bharucha-Goebel et al., 2013; Maggi et al., 2013; Abath Neto et al., 2017; Klein et al., 2012); Published functional studies are suggestive of aberrant splicing (Monnier et al., 2008); In silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 25525159, 30932294, 21062345, 16380615, 18765655, 30611313, 23919265, 16917943, 23553484, 20583297, 22473935, 20839240, 23394784, 18253926, 28818389, Bhanudeep2021[Article], 34440373)
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV001775081	SCV002012482	pathogenic	Central core myopathy	2021-10-13	criteria provided, single submitter	research	ACMG codes: PS3; PS4M; PM2; PM3; PP5
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV000535801	SCV004046372	pathogenic	RYR1-related disorder		criteria provided, single submitter	clinical testing	This variant affects the canonical splice acceptor site of intron 68 and is therefore predicted to interfere with splicing and result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously reported as a compound heterozygous change in patients with congenital myopathy with cores and centronuclear myopathy (PMID: 18253926, 28818389, 30932294, 31069529, 34440373). This variant, in cis with the c.14524G>A (p.Val4842Met) variant, is part of a known haplotype and has been reported as a compound heterozygous change in individuals with RYR1-related myopathies (PMID: 18253926, 20839240). Functional studies demonstrated that the c.10348-6C>G variant resulted in aberrant splicing that introduces a premature termination codon causing the mRNA to undergo NMD (PMID: 18253926, 25525159). The c.10348-6C>G variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.003% (9/282854) and is absent in the homozygous state, thus is presumed to be rare. Based on the available evidence, the c.10348-6C>G variant is classified as Pathogenic.
Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand	RCV000535801	SCV004123105	pathogenic	RYR1-related disorder	2023-07-01	criteria provided, single submitter	research
All of Us Research Program, National Institutes of Health	RCV003997313	SCV004822591	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2023-11-20	criteria provided, single submitter	clinical testing	This variant causes a C to G nucleotide substitution at the -6 position of intron 68 of the RYR1 gene. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with RYR1-related disorders in the literature. This variant has been identified in 9/282854 chromosomes in the general population by the Genome Aggregation Database (gnomAD). This variant has not been reported in individuals affected with autosomal dominant malignant hyperthermia in the literature, although it is associated with other phenotype(s) (ClinVar variation ID: 132994). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV001775081	SCV004847591	pathogenic	Central core myopathy	2022-11-03	criteria provided, single submitter	clinical testing	The c.10348-6C>G variant in RYR1 has been reported in the compound heterozygous state in at least 11 individuals of African descent in cis with p.Val4842Met (suggesting it is a founder variant in Africans) and 2 Chilean individuals with congenital myopathy, and segregated with disease in 4 affected relatives from 2 families (Bharucha-Goebel 2013 PMID: 23553484, Wilmshurst 2010 PMID: 20839240, Monnier 2008 PMID: 18253926, Bevilacqua 2011 PMID: 21062345). It has been reported in ClinVar (Variation ID 132994) and has also been identified in 13/41476 of African chromosomes by gnomAD (http://gnomad.broadinstitute.org). In vitro functional studies (using patient tissue) showed that the c.10348-6C>G variant resulted in a loss of splicing of intron 68 and the introduction of a premature stop codon (p.His3449ins33fsX54). Both unspliced and spliced transcripts were present, thus indicating an incomplete penetrance of this intronic variation (Monnier 2008 PMID: 18253926, Bevilacqua 2011 PMID: 1062345). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive congenital myopathy. ACMG/AMP Criteria applied: PM2_Supporting, PS3_Supporting, PM3_Very strong, PP1.
Muscle and Diseases Team, Institut de Génétique et Biologie Moléculaire et Cellulaire	RCV004586556	SCV005038478	pathogenic	Centronuclear myopathy	2024-03-01	criteria provided, single submitter	research	PS3+PP1_Strong+PM2+PM3
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004689614	SCV005185162	pathogenic	Myopathy, RYR1-associated	2024-05-21	criteria provided, single submitter	clinical testing	Variant summary: RYR1 c.10348-6C>G alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Computational tools predict a significant impact on normal splicing: Two predict the variant weakens a canonical 3' acceptor site. One predicts the variant abolishes this site. At least one publication reports experimental evidence that this variant affects mRNA splicing (Monnier_2008). The variant allele was found at a frequency of 2e-05 in 251458 control chromosomes (gnomAD). c.10348-6C>G has been reported in the literature in individuals affected with Myopathy, RYR1-Associated (e.g. Monnier_2008, Bevilacqua_2011, Abath Neto_2017). These data indicate that the variant is likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 28818389, 18253926, 21062345). ClinVar contains an entry for this variant (Variation ID: 132994). Based on the evidence outlined above, the variant was classified as pathogenic.
Leiden Muscular Dystrophy (RYR1)	RCV000119410	SCV000154317	not provided	not provided		no assertion provided	not provided