ClinVar Miner

Submissions for variant NM_000540.2(RYR1):c.2122G>A (p.Asp708Asn) (rs138874610)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000210007 SCV000265690 uncertain significance Malignant hyperthermia, susceptibility to, 1 2013-07-01 criteria provided, single submitter research
CSER_CC_NCGL; University of Washington Medical Center RCV000148798 SCV000190536 likely benign Congenital myopathy 2014-06-01 no assertion criteria provided research
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000147418 SCV000610201 uncertain significance not provided 2017-05-17 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000243154 SCV000226737 likely benign not specified 2018-07-17 criteria provided, single submitter clinical testing
GeneDx RCV000147418 SCV000565500 uncertain significance not provided 2018-02-08 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the RYR1 gene. The D708N variant was previously reported in cis with a nonsense variant (R2241X), and in trans with an additional RYR1 variant, in an individual with multi-minicore disease (Zhou et al., 2010). D708N was also reported, along with R2241X and an additional RYR1 variant, in two siblings with proximal weakness, ophthalmoparesis, feeding difficulties, and respiratory weakness (Klein et al., 2011; Klein et al., 2012; Amburgey et al., 2013). The D708N variant is observed in 40/10084 (0.4%) alleles from individuals of Ashkenazi Jewish background, including 1 homozygous individual, in large population cohorts (Lek et al., 2016). The D708N variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Missense variants in nearby residues have been reported in the Human Gene Mutation Database in individuals with RYR1-related disorders (Stenson et al., 2014). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Genetic Services Laboratory, University of Chicago RCV000147418 SCV000194815 uncertain significance not provided 2013-11-06 criteria provided, single submitter clinical testing
Invitae RCV000552172 SCV000659881 likely benign RYR1-Related Disorders 2017-12-14 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000243154 SCV000711658 uncertain significance not specified 2017-08-29 criteria provided, single submitter clinical testing Disclaimer: This variant has not undergone full assessment. The following are pr eliminary notes: This variant has been reported in 6 papers in HGMD (classified as DM), with comments suggesting VUS-likely benign. This variant is classified i n ClinVar with 1 star as VUS by University of Chicago, Emory, and Biesecker lab, and is classified as Likely benign by Prevention genetics and CSER_CC_NCGL. The variant has a Max MAF of 0.10% in ExAC (69 alleles) and 0.4% in gnomAD (40 Ashk enazi alleles). Frequency too high for disease incidence. Variant is not present in database.
PreventionGenetics RCV000243154 SCV000304875 likely benign not specified criteria provided, single submitter clinical testing
PreventionGenetics RCV000147418 SCV000852510 likely benign not provided 2017-02-12 criteria provided, single submitter clinical testing

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