Submissions for variant NM_000540.3(RYR1):c.11798A>G (p.Tyr3933Cys)

gnomAD frequency: 0.00108  dbSNP: rs147136339

Total submissions: 23

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000119441	SCV000194792	uncertain significance	not provided	2014-04-29	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000119441	SCV000203471	uncertain significance	not provided	2018-03-01	criteria provided, single submitter	clinical testing
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000148797	SCV000265744	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2013-07-01	criteria provided, single submitter	research
CeGaT Center for Human Genetics Tuebingen	RCV000119441	SCV000575182	uncertain significance	not provided	2024-05-01	criteria provided, single submitter	clinical testing	RYR1: PM3:Strong, PM2, PP3, BS2
Labcorp Genetics (formerly Invitae), Labcorp	RCV000655533	SCV000777464	uncertain significance	RYR1-related disorder	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 3933 of the RYR1 protein (p.Tyr3933Cys). This variant is present in population databases (rs147136339, 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.Tyr3933Cys), 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, 18564801, 20681998, 23558838, 30611313). ClinVar contains an entry for this variant (Variation ID: 133021). 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) performed at Invitae indicates that this missense variant is expected to disrupt RYR1 protein function with a positive predictive value of 95%. 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	RCV000119441	SCV000852270	uncertain significance	not provided	2016-08-15	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000764196	SCV000895199	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	RCV000148797	SCV001141074	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2022-05-20	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001331321	SCV001523338	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	RCV000119441	SCV001715520	uncertain significance	not provided	2020-02-12	criteria provided, single submitter	clinical testing
GeneDx	RCV000119441	SCV001871194	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, 30788618, 30611313, 31321302, 32125936, 25637381, 20681998, 24055113, 25747005, 24950660, 23558838, 25960145, 23919265, 25735680, 22473935, 21674524, 25958340, 28269792, 28259615, 26332594, 25214167, 18564801, 30155738, 25658027, 30932294, 31517061, 32236737, 32403337, 35207755, 33646171, 34008892, 33726816, 32528171, 35428369)
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV001331321	SCV001976679	uncertain significance	Central core myopathy	2021-10-01	criteria provided, single submitter	clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV002251988	SCV002523746	uncertain significance	See cases	2020-07-11	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS4, PM3, PP3
MGZ Medical Genetics Center	RCV000148797	SCV002580952	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2022-07-27	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000119441	SCV003813049	uncertain significance	not provided	2022-11-16	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003398723	SCV004122731	uncertain significance	not specified	2024-05-20	criteria provided, single submitter	clinical testing	Variant summary: RYR1 c.11798A>G (p.Tyr3933Cys) results in a non-conservative amino acid change located in the RyR/IP3R Homology associated domain (IPRIPR013662) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00087 in 251418 control chromosomes. c.11798A>G has been reported in the literature in cis with c.10097G>A and c.4711A>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, 37937776). ClinVar contains an entry for this variant (Variation ID: 133021). Based on the evidence outlined above, the variant was classified as uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000148797	SCV004358201	likely benign	Malignant hyperthermia, susceptibility to, 1	2023-03-20	criteria provided, single submitter	clinical testing
Molecular Genetics, Royal Melbourne Hospital	RCV003993810	SCV004812470	uncertain significance	RYR1-related myopathy	2023-04-11	criteria provided, single submitter	clinical testing	This sequence change in RYR1 is predicted to replace tyrosine with cysteine at codon 3933, p.(Tyr3933Cys). The tyrosine residue is highly conserved (100 vertebrates, UCSC), and is located in exon 86. There is a large physicochemical difference between tyrosine and cysteine. The highest population minor allele frequency in the population database gnomAD v2.1 is 0.13% (172/129,120 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 predict a deleterious effect for the missense substitution (5/5 algorithms). 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: PP3. The haplotype is classified as LIKELY PATHOGENIC. Following criteria are met: PM3_VeryStrong, PP1.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV003993810	SCV005399930	uncertain significance	RYR1-related myopathy	2020-10-19	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as a VUS. Following criteria are met: 0103 - Both loss- and gain-of-function are known mechanisms of disease for this gene (PMID: 23919265) (N) 0108 - This gene is known to be associated with both recessive and dominant disease (OMIM) (N) 0112 - Variants in this gene are known to have reduced penetrance (PMID: 31206373). (N) 0200 - Variant is predicted to result in a missense amino acid change from tyrosine to cysteine (exon 86). (N) 0251 - Variant is heterozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (240 heterozygotes, 0 homozygotes). (P) 0309 - An alternative amino acid change at the same position has been observed in gnomAD: p.(Tyr3933His) (1 heterozygote, 0 homozygotes). (N) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (P) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants. Located in the C-terminal/R3 domain (PMID: 23919265). (P) 0705 - No comparable missense variants have previous evidence for pathogenicity. (N) 0808 - Previous reports of pathogenicity are conflicting. This variant has been reported as VUS (7x), likely benign (1x) and benign (1x) in ClinVar. It has also previously been reported in cis with two additional RYR1 variants (p.(Ile1571Val) and p.(Arg3366His)) in MH susceptible individuals (PMID: 25958340). In addition, these three RYR1 variants have been reported in trans with the pathogenic p.(Val4849Ile) variant in patients with CCD, multiminicore disease, as well as in a patient with core myopathy and MH susceptibility (PMID: 25960145). (N) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign
Leiden Muscular Dystrophy (RYR1)	RCV000119441	SCV000154348	not provided	not provided		no assertion provided	not provided
CSER _CC_NCGL, University of Washington	RCV000148797	SCV000190535	likely benign	Malignant hyperthermia, susceptibility to, 1	2014-06-01	no assertion criteria provided	research
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	RCV000148797	SCV004041719	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2023-10-09	no assertion criteria provided	clinical testing
Undiagnosed Diseases Network, NIH	RCV000655533	SCV005368687	uncertain significance	RYR1-related disorder	2023-02-28	no assertion criteria provided	clinical testing