rs137932199
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS1
This summary comes from the ClinGen Evidence Repository: 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. LINK:https://erepo.genome.network/evrepo/ui/classification/CA023812/MONDO:0007783/012
Frequency
Consequence
NM_000540.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes 0.00111 AC: 169AN: 152194Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.000876 AC: 220AN: 251008Hom.: 0 AF XY: 0.000950 AC XY: 129AN XY: 135752
GnomAD4 exome AF: 0.00117 AC: 1717AN: 1461784Hom.: 3 Cov.: 32 AF XY: 0.00121 AC XY: 878AN XY: 727216
GnomAD4 genome 0.00111 AC: 169AN: 152312Hom.: 0 Cov.: 31 AF XY: 0.00107 AC XY: 80AN XY: 74500
ClinVar
Submissions by phenotype
not provided Uncertain:7Benign:1Other:1
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 (PMID: 25960145, 23919265, 25958340); Patients with only Y3933C and R3366H variants were reported to have malignant hyperthermia susceptibility or to be unaffected (PMID: 25958340, 25960145); 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: 28259615, 30611313, 30788618, 32125936, 24055113, 25658027, 25637381, 26332594, 23069638, 25747005, 24950660, 23919265, 25735680, 25214167, 21674524, 25958340, 22473935, 28269792, 30155738, 30932294, 31517061, 32236737, 32528171, 35428369, 34106485, 33646171, 35207755, 33726816, 34008892, 32403337, 25960145, 37937776, Hiraide2024[casereport], 37643885, 36628841, 36833224) -
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RYR1: PM3:Strong, PM2, PP3, BS2 -
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Malignant hyperthermia, susceptibility to, 1 Uncertain:2Benign:4
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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. -
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Central core myopathy Pathogenic:1Uncertain:1
This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
PM2, PM3, PP2, PP3, PP5 -
RYR1-related disorder Uncertain:2
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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. -
RYR1-related myopathy Uncertain:2
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 arginine to histidine (exon 67). (N) 0251 - Variant is heterozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (243 heterozygotes, 0 homozygotes). (P) 0502 - Missense variant with conflicting in silico predictions and/or uninformative conservation. (N) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (N) 0708 - Comparable variants have conflicting previous evidence for pathogenicity. p.(Arg3366Ser) and p.(Arg3366Leu) each have a single VUS entry in ClinVar (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.(Tyr3933Cys)) 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 -
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. -
not specified Uncertain:1
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. -
King Denborough syndrome;C1850674:Congenital multicore myopathy with external ophthalmoplegia;C2930980:Malignant hyperthermia, susceptibility to, 1;C5830701:Central core myopathy Uncertain:1
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See cases Uncertain:1
ACMG classification criteria: PS4, PM3 -
Congenital myopathy with fiber type disproportion;C1850674:Congenital multicore myopathy with external ophthalmoplegia;C2930980:Malignant hyperthermia, susceptibility to, 1;C5830701:Central core myopathy Uncertain:1
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King Denborough syndrome Uncertain:1
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Multiminicore/minicore/multicore disease Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at