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

dbSNP: rs150396398

Total submissions: 22

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 hip dislocation	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	RCV000584956	SCV000614901	uncertain significance	not provided	2021-08-12	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001080400	SCV000659821	benign	RYR1-related disorder	2024-02-01	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000584956	SCV000692966	benign	not provided	2024-06-01	criteria provided, single submitter	clinical testing	RYR1: BS1, BS2
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001796962	SCV000697407	likely benign	not specified	2023-06-01	criteria provided, single submitter	clinical testing	Variant summary: RYR1 c.13513G>C (p.Asp4505His) results in a non-conservative amino acid change located in the ryanodine receptor TM 4-6 domain (IPR009460) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0034 in 206460 control chromosomes, including 2 homozygotes, and predominantly at a frequency of 0.0054 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is higher than the estimated maximal expected allele frequency for a pathogenic variant in RYR1 causing Malignant Hyperthermia Susceptibility phenotype determined by the ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel (0.0054 vs 0.0038; Johnston_2021), suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.13513G>C has been reported in the literature in individuals affected with malignant hyperthermia susceptibility, King-Denborough syndrome, congenital myopathy, RYR1-related late-onset axial myopathy, core myopathy, idiopathic hyperCKemia and atrioventricular septal defect; however no strong evidences of pathogenicity were found in these studies (e.g. Malandrini_2008, Groom_2011, Klein_2012, Maggi_2013, Loseth_2013, Klingler_2014, Gillies_2015, Priest_2016, Jokela_2019, Elliott_2022, Fusto_2022). Thus, these reports do not provide unequivocal conclusions about association of the variant with Malignant Hyperthermia Susceptibility or other RYR2-related disorders. This variant was found to cause a modest increase in caffeine sensitivity as compared to the wild type protein, and to further enhance such sensitivity when present in cis or trans with another variant, p.R3983C (Groom_2011). Twelve submitters, including the ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, have provided clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as benign (n=2)/likely benign (n=6) or VUS (n=4). Based on the evidence outlined above, the variant was classified as likely benign.
Mendelics	RCV000180740	SCV001141076	benign	Malignant hyperthermia, susceptibility to, 1	2023-08-22	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
Fulgent Genetics, Fulgent Genetics	RCV002477227	SCV002795376	likely benign	Central core myopathy; Malignant hyperthermia, susceptibility to, 1; Congenital multicore myopathy with external ophthalmoplegia; Congenital myopathy with fiber type disproportion; King Denborough syndrome	2022-04-06	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000180740	SCV004358213	benign	Malignant hyperthermia, susceptibility to, 1	2022-09-01	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.
PreventionGenetics, part of Exact Sciences	RCV001080400	SCV000852353	likely benign	RYR1-related disorder	2021-07-16	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
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