ClinVar Miner

Submissions for variant NM_000540.3(RYR1):c.13513G>C (p.Asp4505His)

dbSNP: rs150396398
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Total submissions: 20
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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 RCV000180740 SCV001816187 benign Malignant hyperthermia, susceptibility to, 1 2021-03-17 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 Histidine at codon 4505 of the RYR1 protein, p.(Asp4505His). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.0054, which is considered to be too common for a pathogenic variant causing autosomal dominantly inherited MHS, BA1. This variant has been classified as Benign. Criteria implemented: BA1.
CSER _CC_NCGL, University of Washington RCV000287126 SCV000212212 likely benign Malignant hyperthermia of anesthesia 2015-03-11 criteria provided, single submitter research
Eurofins NTD LLC (GA) RCV000584956 SCV000233225 uncertain significance not provided 2016-07-22 criteria provided, single submitter clinical testing
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000180740 SCV000265748 benign Malignant hyperthermia, susceptibility to, 1 2013-07-01 criteria provided, single submitter research
Illumina Laboratory Services,Illumina RCV000287126 SCV000412979 likely benign Malignant hyperthermia of anesthesia 2016-06-14 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000415198 SCV000492937 uncertain significance Congenital muscular dystrophy; Generalized muscle weakness; EMG: myopathic abnormalities; Congenital dislocation of hip 2014-11-14 criteria provided, single submitter clinical testing
GeneDx RCV000584956 SCV000514428 likely benign not provided 2020-09-14 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 18813041, 23476141, 27147545, 23394784, 22473935, 24195946, 23329375, 25735680, 21918424, 27153395, 26332594, 27058611, 27663056, 28326467, 26019235, 30842289, 32381029)
Athena Diagnostics Inc RCV000584956 SCV000614901 uncertain significance not provided 2018-01-15 criteria provided, single submitter clinical testing
Invitae RCV001080400 SCV000659821 benign RYR1-Related Disorders 2021-12-13 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000584956 SCV000692966 uncertain significance not provided 2021-03-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000584956 SCV000697407 uncertain significance not provided 2016-10-19 criteria provided, single submitter clinical testing Variant summary: The RYR1 c.13513G>C (p.Asp4505His) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant. This variant was found in 281/46630 control chromosomes at a frequency of 0.0060262, which is approximately 69 times the estimated maximal expected allele frequency of a pathogenic RYR1 variant (0.0000875) based on the prevalence of Malignant Hyperthermia Susceptibility, suggesting this variant may be a likely benign polymorphism. However, phenotypes associated with this gene can be silent, generally have a late onset and penetrance of pathogenic variants in this gene are not complete; therefore, the frequency data alone cannot rule out pathogenicity or modifier role. This variant has been reported in patients with Idiopathic hyperCKemia, Malignant Hyperthermia Susceptibility, congenital myopathy, RYR1-related late-onset axial myopathy and atrioventricular septal defect (Malandrini_2008, Groom_2011, Klein_2012, Maggi_2013, Lseth_2013, Klingler_2014, Gillies_2015, Priest_2016); however no strong evidences of pathogenicity were found in these studies. This variant was found to cause modest increase in caffeine sensitivity as compared to wild type, and to further enhance such sensitivity when present in cis or trans with another variant p.R3983C (Groom_2011). A publication reviews available publications including their own and based on the equivocal data presented in the multiple published reports and the low frequency in the EVS, authors categorized the variant as a variant of unknown significance (Gonsalves_2013). Multiple clinical laboratories in ClinVar have classified this variant as VUS/likely benign/benign. Taken together, this variant is currently classified as variant of uncertain significance.
PreventionGenetics,PreventionGenetics RCV001796962 SCV000852353 likely benign not specified 2021-07-12 criteria provided, single submitter clinical testing
Mendelics RCV000180740 SCV001141076 uncertain significance Malignant hyperthermia, susceptibility to, 1 2019-05-28 criteria provided, single submitter clinical testing
Genetic Services Laboratory,University of Chicago RCV001796962 SCV002065946 likely benign not specified 2020-07-07 criteria provided, single submitter clinical testing
CSER _CC_NCGL, University of Washington RCV000148789 SCV000190527 likely benign Myopathy, progressive axial with cataracts 2014-06-01 no assertion criteria provided research
GenomeConnect, ClinGen RCV000287126 SCV000607351 not provided Malignant hyperthermia of anesthesia no assertion provided phenotyping only GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000584956 SCV002033961 likely benign not provided no assertion criteria provided clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) RCV000584956 SCV002036737 likely benign not provided no assertion criteria provided clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000584956 SCV002037340 likely benign not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000584956 SCV002038392 likely benign not provided no assertion criteria provided clinical testing

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