ClinVar Miner

Submissions for variant NM_000540.3(RYR1):c.13513G>C (p.Asp4505His) (rs150396398)

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CSER _CC_NCGL, University of Washington RCV000211491 SCV000212212 likely benign Malignant hyperthermia 2015-03-11 criteria provided, single submitter research
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics 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 Clinical Services Laboratory,Illumina RCV000287126 SCV000412979 likely benign Malignant hyperthermia susceptibility 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 RCV000433256 SCV000514428 likely benign not specified 2018-03-08 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
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 2020-12-07 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000584956 SCV000692966 uncertain significance not provided 2020-10-01 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 RCV000584956 SCV000852353 uncertain significance not provided 2018-03-29 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
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 susceptibility 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.

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