Submissions for variant NM_000540.3(RYR1):c.10097G>A (p.Arg3366His)

gnomAD frequency: 0.00073  dbSNP: rs137932199

Total submissions: 24

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen	RCV000209956	SCV002318982	likely benign	Malignant hyperthermia, susceptibility to, 1	2022-03-14	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 arginine with histidine at codon 3366 of the RYR1 protein, p.(Arg3366His). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.00135, this is considered to be more common than expected for a pathogenic variant causing autosomal dominantly inherited MHS, BS1. This variant has been reported in four unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, all 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) (PMID: 25958340, 25658027, 25735680). However, the high MAF in the NFE population in gnomAD precludes the use of PS4. 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 0.68 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as Likely Benign. Criteria implemented: BS1.
Genetic Services Laboratory, University of Chicago	RCV000119401	SCV000194774	uncertain significance	not provided	2014-04-29	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000119401	SCV000203465	uncertain significance	not provided	2016-06-03	criteria provided, single submitter	clinical testing
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000209956	SCV000265734	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2013-07-01	criteria provided, single submitter	research
CeGaT Center for Human Genetics Tuebingen	RCV000119401	SCV000575179	uncertain significance	not provided	2024-05-01	criteria provided, single submitter	clinical testing	RYR1: PM3:Strong, PM2, PP3, BS2
Labcorp Genetics (formerly Invitae), Labcorp	RCV000655532	SCV000777463	uncertain significance	RYR1-related disorder	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 3366 of the RYR1 protein (p.Arg3366His). This variant is present in population databases (rs137932199, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. Three missense variants, p.Ile1571Val, p.Arg3366His, and p.Tyr3933Cys, which includes this variant (p.Arg3366His), have been reported together in multiple individuals and families affected with RYR1-related disorders including malignant hyperthermia (MH) syndrome, congenital myopathy, central core disease (CCD), and multi minicore disease (MmD). In some cases, the phase of the three variants along with additional RYR1 variants was established, while in other cases it could not be determined. It is therefore unclear if one of the three variants or the additive effect of some or all of these mutations are causative for the RYR1-associated diseases in reported individuals (PMID: 25958340, 25735680, 25214167, 24950660, 25960145, 25658027, 21674524, 30611313). ClinVar contains an entry for this variant (Variation ID: 132990). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
PreventionGenetics, part of Exact Sciences	RCV000119401	SCV000852193	uncertain significance	not provided	2016-08-15	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000764194	SCV000895197	uncertain significance	Central core myopathy; Malignant hyperthermia, susceptibility to, 1; Congenital multicore myopathy with external ophthalmoplegia; Congenital myopathy with fiber type disproportion	2018-10-31	criteria provided, single submitter	clinical testing
Mendelics	RCV000209956	SCV001141069	benign	Malignant hyperthermia, susceptibility to, 1	2019-05-28	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001331317	SCV001523334	uncertain significance	Central core myopathy	2019-05-05	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Mayo Clinic Laboratories, Mayo Clinic	RCV000119401	SCV001715277	uncertain significance	not provided	2020-02-12	criteria provided, single submitter	clinical testing
GeneDx	RCV000119401	SCV001871099	uncertain significance	not provided	2023-05-17	criteria provided, single submitter	clinical testing	Y3933C and R3366H, reported in cis, and in conjunction with an additional RYR1 variant on the opposite allele, have been reported in patients with core myopathies as well as malignant hyperthermia susceptibility in some cases (Amburgey et al., 2013; Kraeva et al., 2015; Snoeck et al., 2015); Patients with only Y3933C and R3366H variants were reported to have malignant hyperthermia susceptibility or to be unaffected (Snoeck et al., 2015; Kraeva et al., 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 36628841, 28259615, 30611313, 30788618, 32125936, 32403337, 24055113, 25658027, 25637381, 26332594, 23069638, 25747005, 24950660, 25960145, 23919265, 25735680, 25958340, 25214167, 21674524, 22473935, 28269792, 30155738, 30932294, 31517061, 32236737, 35207755, 34008892, 33726816, 32528171, 34106485, 33646171, 35428369)
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV001331317	SCV001976678	likely pathogenic	Central core myopathy	2021-10-01	criteria provided, single submitter	clinical testing	PM2, PM3, PP2, PP3, PP5
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV002251987	SCV002523747	uncertain significance	See cases	2020-07-11	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS4, PM3
MGZ Medical Genetics Center	RCV000209956	SCV002580950	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2022-07-27	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000119401	SCV003812493	uncertain significance	not provided	2022-11-16	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003398722	SCV004122730	uncertain significance	not specified	2023-10-11	criteria provided, single submitter	clinical testing	Variant summary: RYR1 c.10097G>A (p.Arg3366His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00088 in 251008 control chromosomes (gnomAD). c.10097G>A has been reported in the literature in cis with c.4711A>G and c.11798A>G in individuals affected with RYR1-Associated Myopathy (malignant hyperthermia (MH), congenital myopathy, central core disease (CCD), and multi minicore disease (MmD) (examples: Duarte_2011, Rocha_2014, Savarese_2014, Fiszer_2015, Snoeck_2015, Gillies_2015, Kraeva_2015, Garibaldi_2019, Granger_2023). It is unclear if one of the three variants or the combined effect of these mutations are causative for the RYR1-associated diseases in reported individuals. The following publications have been ascertained in the context of this evaluation (PMID: 30611313, 21674524, 25658027, 25960145, 24950660, 25214167, 25735680, 25958340, 36628841). Fourteen submitters (including ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel) have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=10), benign/likely benign (n=3) and likely pathogenic(n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000209956	SCV004358177	likely benign	Malignant hyperthermia, susceptibility to, 1	2023-03-20	criteria provided, single submitter	clinical testing
Molecular Genetics, Royal Melbourne Hospital	RCV003993809	SCV004812471	uncertain significance	RYR1-related myopathy	2023-04-11	criteria provided, single submitter	clinical testing	This sequence change in RYR1 is predicted to replace arginine with histidine at codon 3366, p.(Arg3366His). The arginine residue is moderately conserved (100 vertebrates, UCSC), and is located in exon 67. There is a small physicochemical difference between arginine and histidine. The highest population minor allele frequency in the population database gnomAD v2.1 is 0.14% (174/128,896 alleles) in the European (non-Finnish) population. This variant is almost always reported in a haplotype with two other RYR1 missense variants, p.[(Ile1571Val);(Arg3366His);(Tyr3933Cys)]. The haplotype has been detected in at least 19 individuals with a phenotype consistent with RYR1-related myopathy with/without malignant hyperthermia susceptibility (MHS). Of those individuals, 14 were compound heterozygous for the variant and a pathogenic or likely pathogenic variant and 8 of those were confirmed in trans by parental/family testing (PMID: 22473935, 23394784, 24950660, 25958340, 25960145, 30611313, 32236737, 35428369). The haplotype segregates with myopathy in a recessive mode of inheritance in at least one family, and there is conflicting evidence for segregation with MHS (PMID: 22473935, 23394784, 25958340). There is limited evidence that the monoallelic haplotype is associated with RYR1-related disease, it has been detected in individuals that unaffected, with MHS, and symptomatic hyperCKaemia (PMID: 25958340, 28259615, 31517061, 32236737). To our knowledge, the variant has not been detected alone. Multiple lines of computational evidence have conflicting predictions for the missense substitution (3/5 algorithms predict deleterious). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: none. The haplotype is classified as LIKELY PATHOGENIC. Following criteria are met: PM3_VeryStrong, PP1.
Breakthrough Genomics, Breakthrough Genomics	RCV000119401	SCV005207177	likely benign	not provided		criteria provided, single submitter	not provided
Leiden Muscular Dystrophy (RYR1)	RCV000119401	SCV000154308	not provided	not provided		no assertion provided	not provided
CSER _CC_NCGL, University of Washington	RCV000148795	SCV000190533	likely benign	Multiminicore/minicore/multicore disease	2014-06-01	no assertion criteria provided	research
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	RCV003333734	SCV004041718	uncertain significance	King Denborough syndrome	2023-10-09	no assertion criteria provided	clinical testing
Undiagnosed Diseases Network, NIH	RCV000655532	SCV005368685	uncertain significance	RYR1-related disorder	2023-02-28	no assertion criteria provided	clinical testing