19-38457545-C-T
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 14P and 1B. PM5PS3_ModeratePS4PP1_StrongPP3_ModerateBS2_Supporting
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 Cysteine at codon 614 of the RYR1 protein, p.(Arg614Cys). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.00019, a frequency consistent with pathogenicity for MHS. This variant has been reported in over 100 unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, over 100 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 (PMID:24433488, PMID:16163667, PMID:30236257, and others). This variant has been identified in an individual with negative IVCT/CHCT results, BS2_Moderate (PMID:10484775). Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID:26115329). This variant does not reside in a hotspot for pathogenic variants that contribute to MHS (PMID:21118704). Another variant that has been assessed as pathogenic occurs at this codon, p.(Arg614Leu), PM5 (PMID:16917943). p.(Arg614Cys) segregates with MHS in 38 individuals PP1_Strong, (PMID:25960145, PMID:7586638, PMID:11493496 and others). A REVEL score >0.85 supports a pathogenic status for this variant, PP3_Moderate. Criteria implemented: PS3_Moderate, PS4, PM5, PP1_Strong, PP3_Moderate, BS2_Moderate. Based on using Bayes to combine criteria this variant is assessed as Pathogenic, (PMID:29300386). LINK:https://erepo.genome.network/evrepo/ui/classification/CA024311/MONDO:0007783/012
Frequency
Consequence
NM_000540.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 13 ACMG points.
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| RYR1 | ENST00000359596.8 | c.1840C>T | p.Arg614Cys | missense_variant | Exon 17 of 106 | 5 | NM_000540.3 | ENSP00000352608.2 | ||
| RYR1 | ENST00000355481.8 | c.1840C>T | p.Arg614Cys | missense_variant | Exon 17 of 105 | 1 | ENSP00000347667.3 | |||
| RYR1 | ENST00000599547.6 | n.1840C>T | non_coding_transcript_exon_variant | Exon 17 of 80 | 2 | ENSP00000471601.2 |
Frequencies
GnomAD3 genomes 0.000112 AC: 17AN: 152068Hom.: 0 Cov.: 30
GnomAD3 exomes AF: 0.0000875 AC: 22AN: 251496Hom.: 0 AF XY: 0.0000809 AC XY: 11AN XY: 135922
GnomAD4 exome AF: 0.0000691 AC: 101AN: 1461868Hom.: 0 Cov.: 33 AF XY: 0.0000619 AC XY: 45AN XY: 727242
GnomAD4 genome 0.000112 AC: 17AN: 152186Hom.: 0 Cov.: 30 AF XY: 0.0000672 AC XY: 5AN XY: 74390
ClinVar
Submissions by phenotype
Malignant hyperthermia, susceptibility to, 1 Pathogenic:12Other:1
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This missense variant replaces arginine with cysteine at codon 614 of the RYR1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies in HEK293 cells and myotubes have shown cells expressing this variant have increased sensitivity to RYR1 agonists compared to cells expressing wild-type RYR1 (PMID: 9334205, 12732639, 26115329). This variant has been reported in more than 20 individuals and families affected with malignant hyperthermia susceptibility (PMID: 10352931, 11493496, 12411788, 25960145, 23842196, 24433488, 25268394, 25735680, 30236257). It has been shown that this variant segregates with disease in multiple families affected with malignant hyperthermia susceptibility (PMID: 10352931, 11493496, 12411788, 25960145). A different variant affecting the same codon, c.1841G>T (p.Arg614Leu), is considered to be disease-causing (ClinVar variation ID: 133108), suggesting that Arg at this position is important for the protein function. This variant has been described as a common variant associated with malignant hyperthermia in the Western European population (PMID: 11668625, 21455645). This variant has been identified in 30/282862 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -
ACMG codes:PS4M, PM2, PM5, PP3, PP5 -
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Criteria applied: PS4,PP1_STR,PS3_MOD,PM5,PP3_MOD,BS2_MOD -
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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 Cysteine at codon 614 of the RYR1 protein, p.(Arg614Cys). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.00019, a frequency consistent with pathogenicity for MHS. This variant has been reported in over 100 unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, over 100 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 (PMID:24433488, PMID:16163667, PMID:30236257, and others). This variant has been identified in an individual with negative IVCT/CHCT results, BS2_Moderate (PMID:10484775). Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID:26115329). This variant does not reside in a hotspot for pathogenic variants that contribute to MHS (PMID: 21118704). Another variant that has been assessed as pathogenic occurs at this codon, p.(Arg614Leu), PM5 (PMID:16917943). p.(Arg614Cys) segregates with MHS in 38 individuals PP1_Strong, (PMID:25960145, PMID:7586638, PMID:11493496 and others). A REVEL score >0.85 supports a pathogenic status for this variant, PP3_Moderate. Criteria implemented: PS3_Moderate, PS4, PM5, PP1_Strong, PP3_Moderate, BS2_Moderate. Based on using Bayes to combine criteria this variant is assessed as Pathogenic, (PMID: 29300386). -
This missense variant replaces arginine with cysteine at codon 614 of the RYR1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies in HEK293 cells and myotubes have shown cells expressing this variant have increased sensitivity to RYR1 agonists compared to cells expressing wild-type RYR1 (PMID: 9334205, 12732639, 26115329). This variant has been reported in more than 20 individuals and families affected with malignant hyperthermia susceptibility (PMID: 10352931, 11493496, 12411788, 25960145, 23842196, 24433488, 25268394, 25735680, 30236257). It has been shown that this variant segregates with disease in multiple families affected with malignant hyperthermia susceptibility (PMID: 10352931, 11493496, 12411788, 25960145). A different variant affecting the same codon, c.1841G>T (p.Arg614Leu), is considered to be disease-causing (ClinVar variation ID: 133108), suggesting that Arg at this position is important for the protein function. This variant has been described as a common variant associated with malignant hyperthermia in the Western European population (PMID: 11668625, 21455645). This variant has been identified in 30/282862 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene and are associated with RYR1-related disorders (OMIM). Gain of function mechanism has been described in the context of malignant hyperthermia susceptibility 1 (MIM#145600) and autosomal dominant congenital myopathy 1A with susceptibility to malignant hyperthermia (MIM#117000). Autosomal recessive congenital myopathy 1B (MIM#255320) is associated with a loss of function mechanism (PMIDs: 27855725, 23919265). The mechanism of King-Denborough syndrome (MIM#619542) is unclear. (I) 0108 - This gene is associated with both recessive and dominant disease (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 (v2 & v3: 43 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2 & v3: 11 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated RIH domain (DECIPHER), within a region enriched for variants in association with malignant hyperthermia susceptibility and central core disease (PMID: 30406384). (I) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. It is a well-known pathogenic variant associated with malignant hyperthermia susceptibility (ClinVar). In addition, it has been detected in individuals with myopathies (PMID: 21795085, 33458582). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
This sequence change in RYR1 is predicted to replace arginine with cysteine at codon 614, p.(Arg614Cys). The arginine residue is highly conserved (100 vertebrates, UCSC), and is located in exon 17 in the N-terminal region, amino acids 1-552, which is defined as a mutational hotspot. There is a large physicochemical difference between arginine and cysteine. The highest population minor allele frequency in gnomAD v2.1 is 0.02% (25/129,186 alleles) in the European (non-Finnish) population. The prevalence of the variant in individuals with malignant hyperthermia susceptibility (MHS) is significantly increased compared with the prevalence in controls (Odds Ratio 51.1, 95% CI: 26.4-98.7) (PMID: 30236257; gnomAD v2.1 European non-Finnish). It has also been identified in cases with dominant and recessive central core disease, severe statin myopathy, and recurrent rhabdomyolysis (PMID: 14985404, 21795085, 29635721, 33458582). The variant has been reported to segregate with MHS in multiple families (PMID: 8602662, 11493496, 12411788). The variant demonstrates a gain of function effect on intracellular calcium release in a HEK293 assay indicating that this variant impacts protein function (PMID: 9334205). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (5/5 algorithms). Another missense variant c.1841G>T, p.(Arg614Leu) in the same codon has been classified as pathogenic for MHS (ClinVar Variation ID: 133108). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as PATHOGENIC. Following criteria are met: PS4, PP1_Strong, PS3_Moderate, PM1, PM5, PP3. -
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This c.1840C>T (p.Arg614Cys) variant in the RYR1 gene has been reported in multiple unrelated individuals with malignant hyperthermia (PMID: 1774074, 7762556, 10051009, 10484775, 19648156, 23842196, 11668625) or myopathy (PMID: 21795085). This variant has been shown to segregate with features of malignant hyperthermia in multiple families (PMID: 7762556, 7586638, 9520251). The c.796G>A variant is rare in the general population and arginine at position 614 of the RYR1 protein is highly evolutionarily conserved. The c.1840C>T (p.Arg614Cys) variant in the RYR1 gene is classified as pathogenic. -
not provided Pathogenic:7Other:1
One of the most commonly identified RYR1 variants among individuals of Western European backgrounds (Rueffert et al., 2002; Kraeva et al., 2011); Published functional studies demonstrate a damaging effect, as the variant is sufficient to induce malignant hyperthermic episodes by causing impaired calcium and magnesium inhibition and reduced activation of the mutant protein at calcium concentrations typical of normal myotubes at rest (Tong et al., 1997; Yang et al., 2003); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); 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: 21455645, 25637381, 7511586, 30325262, 12124989, 31206373, 24195946, 9334205, 21795085, 12732639, 11668625, 9873004, 23842196, 12059893, 1774074, 19648156, 8602662, 12411788, 29635721, 29382405, 30788618, 30499100, 30236257, 29730239, 30208288, 30611313, 31016048, 31447099, 33278783, 33259453, 31589614, 10352931, 33587123, 14500992, 11493496, 11553045, 32665702, 10756965, 25214167, 32528171) -
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RYR1: PP1:Strong, PS3, PS4, PM5, PP3 -
RYR1-related disorder Pathogenic:3
The RYR1 gene is constrained against missense variation (Z-score= 4.01), and missense variants are a common mechanism of disease (PMID: 20301325). The c.1840C>T (p.Arg614Cys) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. This is a known Pathogenic variant that has been previously reported as a heterozygous change in individuals with malignant hyperthermia (PMID: 1774074, 1510267, 8602662, 30236257, 11493496, 19648156, 23842196). This variant has also been reported as a heterozygous (PMID: 35428369) and compound heterozygous change (PMID: 35627144, 12937085, 33458582) in individuals with congenital RYR1-related myopathies. A different amino acid change at the same residue (p.Arg614Leu) have been previously reported in individuals with malignant hyperthermia (PMID: 9389851, 30236257, 33625594). Functional studies demonstrated increased sensitivity to caffeine and halothane, which has been correlated with calcium release, compared to the wild type protein (PMID: 9334205, 12732639). The c.1840C>T (p.Arg614Cys) variant is present in the heterozygous state in the gnomAD v4 population database at a frequency of 0.007% (118/1614054), and is absent in the homozygous state. Based on the available evidence, c.1840C>T (p.Arg614Cys) is classified as Pathogenic. -
The RYR1 c.1840C>T variant is predicted to result in the amino acid substitution p.Arg614Cys. This variant has been conclusively established to be causative for malignant hyperthermia (MH) (www.emhg.org; Gillard et al. 1991. PubMed ID: 1774074; Otsu et al. 1994. PubMed ID: 7511586; Quane et al. 1997. PubMed ID: 9389851; Tong et al. 1997. PubMed ID: 9334205; Robinson et al. 2006. PubMed ID: 16917943). Functional studies in HEK293 cells indicate this variant results in increased caffeine sensitivity and abnormal ryanodine receptor function (Referred to R615C in Murayama et al. 2015. PubMed ID: 26115329). A different substitution at the same amino acid has also been reported to be causative (p.Arg614Leu). An expert ClinGen MH panel has classified this variant as pathogenic for MH (www.ncbi.nlm.nih.gov/clinvar/variation/12964). This variant is reported in 0.019% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. THIS PATIENT IS SUSCEPTIBLE TO MALIGNANT HYPERTHERMIA! Alternative anesthetics should be used. The patient should consider wearing an ID bracelet or other alert device (see www.mhaus.org). -
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 614 of the RYR1 protein (p.Arg614Cys). This variant is present in population databases (rs118192172, gnomAD 0.02%). This missense change has been observed in individuals with autosomal dominant malignant hyperthermia (PMID: 1774074, 8602662, 10352931, 11493496, 11668625, 12411788, 19648156, 21455645, 21795085, 23842196). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12964). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt RYR1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects RYR1 function (PMID: 9334205, 11668625, 12732639). For these reasons, this variant has been classified as Pathogenic. -
Malignant hyperthermia of anesthesia Pathogenic:2
The p.Arg614Cys variant in RYR1 has been reported in >30 individuals with malignant hyperthermia, and segregated with disease in more than 6 affected relatives from more than 3 families (Gillard 1991, Hogan 1992, Serfas 1996, Fortunato 1999, Rueffert 2001, Girard 2001, Muniz 2003, Vladutiu 2011, Klingler 2014, LMM unpublished data). In vitro functional studies provide some evidence that the p.Arg614Cys variant may impact protein function (Tong 1999, 2003, Girard 2001). Animal models in pigs further support a contribution to malignant hyperthermia (Ostu 1991). This variant has been identified in 0.02% (24/126704) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Please note that for diseases with clinical variability or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. In summary, this variant meets criteria to be classified as pathogenic for malignant hyperthermia in an autosomal dominant manner. ACMG/AMP Criteria applied: PS3, PS4, PP1_Moderate. -
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Inborn genetic diseases Pathogenic:1
The c.1840C>T (p.R614C) alteration is located in coding exon 17 of the RYR1 gene. This alteration results from a C to T substitution at nucleotide position 1840, causing the arginine (R) at amino acid position 614 to be replaced by a cysteine (C). Based on data from gnomAD, the T allele has an overall frequency of 0.011% (30/282862) total alleles studied. The highest observed frequency was 0.019% (25/129186) of European (non-Finnish) alleles. Multiple individuals with this alteration have been reported with MH (Rueffert, 2001A; Rueffert, 2001B; Carpenter, 2009; Gonsalves, 2013). Two siblings were described with this variant in trans with p.G215E with severe presentation of CCD with muliple arthryogyposis, severe hypotonia and amyotrophy, respiratory mechanical assistance, and multiple malformations including short femurs, facial dysmorphims, and bilateral clinodactyly of the second and fifth fingers (Romero, 2003). At 9 years of age the older child had delayed motor development, ptosis, strabismus, scoliosis and amyotrophy (Romero, 2003). The younger brother died at 32 weeks gestation with severe CCD congenital myopathy as well (Romero, 2003). Another alteration at the same codon, c.1841G>T (p.R614L), has been detected in individuals with a positive IVCT test and MH diagnosis (Barone, 1999). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -
Congenital myopathy with fiber type disproportion;C1840365:King Denborough syndrome;C1850674:Congenital multicore myopathy with external ophthalmoplegia;C2930980:Malignant hyperthermia, susceptibility to, 1;C5830701:Central core myopathy Pathogenic:1
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methoxyflurane response - Toxicity Other:1
PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance. Drug-variant association: Toxicity
sevoflurane response - Toxicity Other:1
PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance. Drug-variant association: Toxicity
isoflurane response - Toxicity Other:1
PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance. Drug-variant association: Toxicity
enflurane response - Toxicity Other:1
PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance. Drug-variant association: Toxicity
halothane response - Toxicity Other:1
PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance. Drug-variant association: Toxicity
desflurane response - Toxicity Other:1
PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance. Drug-variant association: Toxicity
succinylcholine response - Toxicity Other:1
PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance. Drug-variant association: Toxicity
Computational scores
Source:
Splicing
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