ClinVar Miner

Submissions for variant NM_000540.3(RYR1):c.2122G>A (p.Asp708Asn) (rs138874610)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel,ClinGen RCV000210007 SCV001816150 uncertain significance Malignant hyperthermia, susceptibility to, 1 2021-03-18 reviewed by expert panel curation This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions. This sequence variant predicts a substitution of Aspartic acid with Asparagine at codon 708 of the RYR1 protein, p.(Asp708Asn). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.0007, a frequency consistent with pathogenicity for MHS. This variant has been reported in individuals with congenital myopathies inherited in an autosomal recessive pattern. No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score of 0.726 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. No criteria were implemented.
Genetic Services Laboratory, University of Chicago RCV000147418 SCV000194815 uncertain significance not provided 2013-11-06 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
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
PreventionGenetics,PreventionGenetics RCV000243154 SCV000304875 likely benign not specified criteria provided, single submitter clinical testing
GeneDx RCV000147418 SCV000565500 likely benign not provided 2020-10-15 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 26245150, 29298851, 30155738, 23553787, 25637381, 23919265, 22473935, 21911697, 20080402, 24195946, 20839240, 32236737)
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
Invitae RCV001087371 SCV000659881 likely benign RYR1-Related Disorders 2020-11-14 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 emhg.org database.
PreventionGenetics,PreventionGenetics RCV000147418 SCV000852510 likely benign not provided 2017-02-12 criteria provided, single submitter clinical testing
Mendelics RCV000210007 SCV001141054 benign Malignant hyperthermia, susceptibility to, 1 2019-05-28 criteria provided, single submitter clinical testing
CSER _CC_NCGL, University of Washington RCV000148798 SCV000190536 likely benign Congenital myopathy 2014-06-01 no assertion criteria provided research

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