Submissions for variant NM_000540.3(RYR1):c.38T>G (p.Leu13Arg)

dbSNP: rs193922744

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen	RCV001588945	SCV001816159	likely pathogenic	Malignant hyperthermia, susceptibility to, 1	2023-04-07	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 leucine with arginine at codon 13 of the RYR1 protein, p.(Leu13Arg). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in three unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, two of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Moderate (PMID:19191329; PMID:30236257; PMID:16732084). Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID: 341427251). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). This variant segregates with MHS in three individuals ,PP1 (PMID:19191329, personal communication, RYR1/MHS_VCEP). A REVEL score of 0.828 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as Likely Pathogenic. Criteria implemented: PS3_Moderate, PS4_Moderate, PM1, PP1.
PreventionGenetics, part of Exact Sciences	RCV000119614	SCV000852592	uncertain significance	not provided	2015-07-14	criteria provided, single submitter	clinical testing
Invitae	RCV001854581	SCV002214106	pathogenic	RYR1-related disorder	2023-04-17	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects RYR1 function (PMID: 34127251). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RYR1 protein function. ClinVar contains an entry for this variant (Variation ID: 133129). This missense change has been observed in individual(s) with malignant hyperthermia and/or malignant hyperthermia susceptibility (PMID: 16917943, 19191329, 23558838, 25960145, 34127251). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 13 of the RYR1 protein (p.Leu13Arg).
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000119614	SCV004563682	likely pathogenic	not provided	2023-06-28	criteria provided, single submitter	clinical testing	The RYR1 c.38T>G; p.Leu13Arg variant (rs193922744) is reported in the literature in individuals affected with malignant hyperthermia susceptibility (Brandom 2013, Ibarra 2006, Levano 2009, Robinson 2006, Snoeck 2015, van den Bersselaar 2021) and is also reported in ClinVar (Variation ID: 133129). Additionally, in vitro functional analyses in HEK293 cells demonstrate hypersensitivity to RYR1 agonists (van den Bersselaar 2021). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.828). Based on available information, this variant is considered to be likely pathogenic. References: Brandom BW et al. Ryanodine receptor type 1 gene variants in the malignant hyperthermia-susceptible population of the United States. Anesth Analg. 2013 May;116(5):1078-1086. PMID: 23558838. Ibarra M CA et al. Malignant hyperthermia in Japan: mutation screening of the entire ryanodine receptor type 1 gene coding region by direct sequencing. Anesthesiology. 2006 Jun;104(6):1146-54. PMID: 16732084. Levano S et al. Increasing the number of diagnostic mutations in malignant hyperthermia. Hum Mutat. 2009 Apr;30(4):590-8. PMID: 19191329. Robinson R et al. Mutations in RYR1 in malignant hyperthermia and central core disease. Hum Mutat. 2006 Oct;27(10):977-89. PMID: 16917943. Snoeck M et al. RYR1-related myopathies: a wide spectrum of phenotypes throughout life. Eur J Neurol. 2015 Jul;22(7):1094-112. PMID: 25960145. van den Bersselaar LR et al. RYR1 variant c.38T>G, p.Leu13Arg causes hypersensitivity of the ryanodine receptor-1 and is pathogenic for malignant hyperthermia. Br J Anaesth. 2021 Aug;127(2):e63-e65. PMID: 34127251.
Institute of Human Genetics, University of Leipzig Medical Center	RCV001588945	SCV004812132	likely pathogenic	Malignant hyperthermia, susceptibility to, 1	2024-03-26	criteria provided, single submitter	clinical testing	Criteria applied: PS3_MOD,PS4_MOD,PM1,PP1
Leiden Muscular Dystrophy (RYR1)	RCV000119614	SCV000154521	not provided	not provided		no assertion provided	not provided