NM_000540.3(RYR1):c.7300G>A (p.Gly2434Arg) AND Malignant hyperthermia, susceptibility to, 1
- Germline classification:
- Pathogenic (7 submissions)
- Last evaluated:
- Jul 11, 2022
- Review status:
- 3 stars out of maximum of 4 starsreviewed by expert panel
- Somatic classification
of clinical impact: - None
- Review status:
- (0/4) 0 stars out of maximum of 4 starsno assertion criteria provided
- Somatic classification
of oncogenicity: - None
- Review status:
- (0/4) 0 stars out of maximum of 4 starsno assertion criteria provided
- Record status:
- current
- Accession:
- RCV000013837.24
Allele description [Variation Report for NM_000540.3(RYR1):c.7300G>A (p.Gly2434Arg)]
NM_000540.3(RYR1):c.7300G>A (p.Gly2434Arg)
- Gene:
- RYR1:ryanodine receptor 1 [Gene - OMIM - HGNC]
- Variant type:
- single nucleotide variant
- Cytogenetic location:
- 19q13.2
- Genomic location:
- Preferred name:
- NM_000540.3(RYR1):c.7300G>A (p.Gly2434Arg)
- Other names:
- NM_000540.3(RYR1):c.7300G>A
- HGVS:
- NC_000019.10:g.38499993G>A
- NG_008866.1:g.71294G>A
- NM_000540.3:c.7300G>AMANE SELECT
- NM_001042723.2:c.7300G>A
- NP_000531.2:p.Gly2434Arg
- NP_000531.2:p.Gly2434Arg
- NP_001036188.1:p.Gly2434Arg
- LRG_766t1:c.7300G>A
- LRG_766:g.71294G>A
- LRG_766p1:p.Gly2434Arg
- NC_000019.9:g.38990633G>A
- NM_000540.2:c.7300G>A
- P21817:p.Gly2434Arg
- p.(Gly2434Arg)
This HGVS expression did not pass validation- Protein change:
- G2434R; GLY2434ARG
- Links:
- PharmGKB: 1183705812PA164749136; PharmGKB: 1183705812PA449461; PharmGKB: 1183705812PA449845; PharmGKB: 1183705812PA450106; PharmGKB: 1183705812PA450434; PharmGKB: 1183705812PA451341; PharmGKB: 1183705812PA451522; UniProtKB: P21817#VAR_005605; OMIM: 180901.0007; dbSNP: rs121918593
- NCBI 1000 Genomes Browser:
- rs121918593
- Molecular consequence:
- NM_000540.3:c.7300G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001042723.2:c.7300G>A - missense variant - [Sequence Ontology: SO:0001583]
- Observations:
- 10
Condition(s)
- Name:
- Malignant hyperthermia, susceptibility to, 1 (MHS1)
- Synonyms:
- Anesthesia related hyperthermia; Malignant hyperpyrexia; Fulminating hyperpyrexia; See all synonyms [MedGen]
- Identifiers:
- MONDO: MONDO:0007783; MedGen: C2930980; Orphanet: 423; OMIM: 145600
Assertion and evidence details
| Submission Accession | Submitter | Review Status (Assertion method) | Clinical Significance (Last evaluated) | Origin | Method | Citations |
|---|---|---|---|---|---|---|
| SCV000034084 | OMIM | no assertion criteria provided | risk factor (Feb 21, 1997) | germline | literature only | |
| SCV000778611 | HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology - AGHI_GT | criteria provided, single submitter (ACMG Guidelines, 2015) | Pathogenic (Feb 28, 2020) | unknown | research | |
| SCV000840061 | Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine | criteria provided, single submitter (ACMG Guidelines, 2015) | Pathogenic (May 25, 2017) | germline | clinical testing | |
| SCV001429341 | Institute of Human Genetics, University of Leipzig Medical Center | criteria provided, single submitter (ACMG Guidelines, 2015) | Pathogenic (Dec 10, 2019) | germline | clinical testing | |
| SCV002570137 | ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen | reviewed by expert panel (ClinGen MHS ACMG Specifications V2) | Pathogenic (Jul 11, 2022) | germline | curation | |
| SCV004358126 | Color Diagnostics, LLC DBA Color Health | criteria provided, single submitter (ACMG Guidelines, 2015) | Pathogenic (Mar 1, 2023) | germline | clinical testing | |
| SCV004820910 | All of Us Research Program, National Institutes of Health | criteria provided, single submitter (ACMG Guidelines, 2015) | Pathogenic (Jan 8, 2024) | germline | clinical testing |
Summary from all submissions
| Ethnicity | Origin | Affected | Individuals | Families | Chromosomes tested | Number Tested | Family history | Method |
|---|---|---|---|---|---|---|---|---|
| not provided | germline | yes | 1 | not provided | not provided | not provided | not provided | clinical testing |
| not provided | germline | not provided | not provided | not provided | not provided | not provided | not provided | literature only |
| not provided | germline | unknown | 9 | not provided | not provided | 108544 | not provided | clinical testing, curation |
| not provided | unknown | unknown | 6 | not provided | not provided | 6 | not provided | research |
Citations
PubMed
The structural organization of the human skeletal muscle ryanodine receptor (RYR1) gene.
Phillips MS, Fujii J, Khanna VK, DeLeon S, Yokobata K, de Jong PJ, MacLennan DH.
Genomics. 1996 May 15;34(1):24-41.
- PMID:
- 8661021
Klingler W, Heiderich S, Girard T, Gravino E, Heffron JJ, Johannsen S, Jurkat-Rott K, Rüffert H, Schuster F, Snoeck M, Sorrentino V, Tegazzin V, Lehmann-Horn F.
Orphanet J Rare Dis. 2014 Jan 16;9:8. doi: 10.1186/1750-1172-9-8.
- PMID:
- 24433488
- PMCID:
- PMC3896768
Details of each submission
From OMIM, SCV000034084.6
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | literature only | PubMed (3) |
Description
In affected individuals from 4 of 104 unrelated families with malignant hyperthermia susceptibility (MHS1; 145600), Keating et al. (1994) identified a heterozygous gly2433-to-arg (GLY2433ARG) change in the RYR1 gene resulting from a c.7297G-A transition. The authors noted that this mutation is adjacent to the R2434H mutation (180901.0003), which may indicate a second cluster in the RYR1 gene where MHS and/or central core disease (CMYO1A; 117000) mutations occur.
In the numbering system of amino acids provided by the corrected sequence data for human RYR1 according to Phillips et al. (1996), this mutation was referred to as G2434R by Richter et al. (1997). Functional studies showed that the G2434R mutation enhanced the sensitivity of RYR1 to activating concentrations of calcium and to caffeine. In parallel, the sensitivity to inhibiting concentrations of calcium and calmodulin was reduced, transferring the mutant calcium-release channel into a hyperexcitable state.
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | germline | not provided | not provided | not provided | not provided | not provided | not provided | not provided | not provided | |
From HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology - AGHI_GT, SCV000778611.2
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | 1 | not provided | not provided | research | PubMed (1) |
| 2 | not provided | 1 | not provided | not provided | research | PubMed (1) |
| 3 | not provided | 1 | not provided | not provided | research | PubMed (1) |
| 4 | not provided | 1 | not provided | not provided | research | PubMed (1) |
| 5 | not provided | 1 | not provided | not provided | research | PubMed (1) |
| 6 | not provided | 1 | not provided | not provided | research | PubMed (1) |
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | unknown | unknown | 1 | not provided | not provided | 1 | not provided | not provided | not provided | |
| 2 | unknown | unknown | 1 | not provided | not provided | 1 | not provided | not provided | not provided | |
| 3 | unknown | unknown | 1 | not provided | not provided | 1 | not provided | not provided | not provided | |
| 4 | unknown | unknown | 1 | not provided | not provided | 1 | not provided | not provided | not provided | |
| 5 | unknown | unknown | 1 | not provided | not provided | 1 | not provided | not provided | not provided | |
| 6 | unknown | unknown | 1 | not provided | not provided | 1 | not provided | not provided | not provided | |
From Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine, SCV000840061.1
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | clinical testing | PubMed (1) |
Description
This c.7300G>A (p.Gly2434Arg) variant in the RYR1 gene has previously been reported in multiple patients with malignant hyperthermia [PMID 7849712, 23842196, 19648156, 11668625]. This variant has been functionally characterized and shown to have an increased sensitivity to activating concentrations of Ca2+ and to caffeine and 4-chloro-m-cresol in vitro. The variant is classified as pathogenic by the European malignant hyperthermia group (https://emhg.org). This variant has been observed in one 3 heterozygous individual from the ExAC database (http://exac.broadinstitute.org/variant/19-38990633-G-A). Glycine at position 2434 of the RYR1 protein is highly conserved. While not clinically validated, computer-based algorithms SIFT and Polyphen2 predict this p.Gly2434Arg change to be deleterious. It is thus interpreted as a pathogenic variant.
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | germline | unknown | not provided | not provided | not provided | not provided | not provided | not provided | not provided | |
From Institute of Human Genetics, University of Leipzig Medical Center, SCV001429341.1
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | 1 | not provided | not provided | clinical testing | PubMed (1) |
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | germline | yes | not provided | not provided | not provided | 1 | not provided | not provided | not provided | |
From ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen, SCV002570137.1
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | curation | not provided |
Description
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 glycine with arginine at codon 2434 of the RYR1 protein, p.(Gly2434Arg). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.000078, a frequency consistent with pathogenicity for MHS. This variant has been reported in 178 unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, 174 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: 30236257, 10484775, 23558838, 16163667, 21455645, 23842196, 7849712, 7881417, 11575529, 15731587, 11668625, 12059893, 12151923, 31559918, 10700782, 17081125, 18564801, 20681998, 21965348, 23460944, 25735680, 25960145, 9030597, 25268394, 17667681). This variant has been identified in six individuals with negative IVCT/CHCT results, BS2 (PMID:30236257). A functional study in HEK293 cells shows an increased sensitivity to RYR1 agonists (PMID: 27586648). p.(Gly2434Arg) knock-in mice are susceptible to malignant hyperthermia due to volatile anesthetics and ex vivo assays demonstrate increased sensitivity to RYR1 agonists for knock-in myotubes, PS3 (PMID:30236258). 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 at least 20 individuals, PP1_Strong (PMID: 7849712, 11575529, 12059893, 25960145). A REVEL score >0.85 (0.956) supports a pathogenic status for this variant, PP3_Moderate. Based on using Bayes to combine criteria this variant is assessed as Pathogenic, (PMID: 29300386). Criteria implemented: PS3, PS4, PM1, PP1_Strong, PP3_Moderate, BS2.
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | germline | unknown | not provided | not provided | not provided | not provided | not provided | not provided | not provided | |
From Color Diagnostics, LLC DBA Color Health, SCV004358126.1
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | clinical testing | PubMed (13) |
Description
This missense variant replaces glycine with arginine at codon 2434 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). A study using genetically engineered mice has shown that mice carrying this variant develop malignant hyperthermia when exposed to halothane (PMID: 30236258). Further, functional studies on myotubes from the genetically engineered mice showed increased sensitivity to caffeine, halothane, and KCI in comparison to myotubes expressing wild-type RYR1 (PMID: 30236258). This variant has been reported in over 100 families and individuals affected with malignant hyperthermia susceptibility (PMID: 21455645, 23558838, 23842196, 24433488, 25268394, 25735680, 25960145, 27646467, 30236257, 30788618, 31206373). This variant has been identified in 11/282648 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | germline | unknown | not provided | not provided | not provided | not provided | not provided | not provided | not provided | |
From All of Us Research Program, National Institutes of Health, SCV004820910.1
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | 9 | not provided | not provided | clinical testing | PubMed (29) |
Description
The c.7300G>A (p.Gly2434Arg) variant, located on the exon 45 of the RYR1 gene, replaces glycine with arginine at codon 2434 of the RYR1 protein (p.Gly2434Arg). This missense change has been observed in >100 individuals with personal or family histories of a malignant hyperthermia reaction, positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) (PMID: 30236257, 10484775, 23558838, 16163667, 21455645, 23842196, 7849712, 7881417, 11575529, 15731587, 11668625, 12059893, 12151923, 31559918, 10700782, 17081125, 18564801, 20681998, 21965348, 23460944, 25735680, 25960145, 9030597, 25268394, 17667681). This variant segregates with malignant hyperthermia (MHS) in at least 20 individuals (PMID: 7849712, 11575529, 12059893, 25960145). This missense variant is located in a mutational hot spot region that contributes to MHS (PMID: 21118704). A functional study in HEK293 cells shows an increased sensitivity to RYR1 agonists (PMID: 27586648). Such effect was confirmed in human skeletal muscle specimens isolated from MHS individuals carrying this RYR1 variant (PMID:9030597). Additionally, p.Gly2434Arg knock-in mice are susceptible to malignant hyperthermia due to volatile anesthetics, and ex vivo assays demonstrate increased sensitivity to RYR1 agonists for knock-in myotubes (PMID:30236258). Computational prediction (REVEL >0.85) suggests that this variant may have deleterious impact on protein structure and function. For these reasons, the c.7300G>A (p.Gly2434Arg) variant of RYR1 is classified as pathogenic.
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | germline | unknown | 108544 | not provided | not provided | 9 | not provided | not provided | not provided | |
Last Updated: Nov 3, 2024