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 341 of the RYR1 protein p.(Gly341Arg), c.1021G>A. This variant is not present in a large population database (gnomAD). This variant has been reported in 71 unrelated probands who have a personal or family history of a malignant hyperthermia reaction and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (when the proband was unavailable for testing a positive diagnostic test result in a mutation positive relative was counted), PS4 ( PMID:30236257, PMID:16163667, PMID: 8012359 and others). Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID:26115329). 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 66 individuals, PP1_Strong ( PMID: 8012359, PMID:9106529, PMID:17710899 and others). A REVEL score > 0.85 supports pathogenicity,PP3_Moderate. Based on using Bayes to combine criteria this variant is assessed as Pathogenic, (PMID: 29300386). Criteria implemented: PS4, PS3_Moderate, PM1, PP1_Strong, PP3_Moderate, BS2_Moderate.
ClinVar Genomic variation as it relates to human health
NM_000540.3(RYR1):c.1021G>A (p.Gly341Arg)
Germline
Top reviewed classifications are shown here.
Submission summary:
Reviewed by expert panel
Pathogenic
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000540.3(RYR1):c.1021G>A (p.Gly341Arg)
Variation ID: 12969 Accession: VCV000012969.24
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 19q13.2 19: 38448712 (GRCh38) [ NCBI UCSC ] 19: 38939352 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Jun 9, 2014 Sep 29, 2024 Mar 18, 2021 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000540.3:c.1021G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000531.2:p.Gly341Arg missense NM_001042723.2:c.1021G>A NP_001036188.1:p.Gly341Arg missense NC_000019.10:g.38448712G>A NC_000019.9:g.38939352G>A NG_008866.1:g.20013G>A LRG_766:g.20013G>A LRG_766t1:c.1021G>A LRG_766p1:p.Gly341Arg P21817:p.Gly341Arg - Protein change
- G341R
- Other names
-
NM_000540.3(RYR1):c.1021G>A
- Canonical SPDI
- NC_000019.10:38448711:G:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Trans-Omics for Precision Medicine (TOPMed) 0.00000
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| RYR1 | No evidence available | No evidence available |
GRCh38 GRCh37 |
8944 | 9259 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic (5) |
reviewed by expert panel
|
Mar 18, 2021 | RCV000013836.19 | |
| Pathogenic/Likely pathogenic (6) |
criteria provided, multiple submitters, no conflicts
|
Jun 23, 2022 | RCV000119406.25 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jan 13, 2024 | RCV000655541.16 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Mar 18, 2021)
|
reviewed by expert panel
Method: curation
|
Malignant hyperthermia, susceptibility to, 1
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen
FDA Recognized Database
Study: ClinGen Accession: SCV001816165.1 First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 |
Comment:
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 … (more)
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 341 of the RYR1 protein p.(Gly341Arg), c.1021G>A. This variant is not present in a large population database (gnomAD). This variant has been reported in 71 unrelated probands who have a personal or family history of a malignant hyperthermia reaction and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (when the proband was unavailable for testing a positive diagnostic test result in a mutation positive relative was counted), PS4 ( PMID:30236257, PMID:16163667, PMID: 8012359 and others). Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID:26115329). 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 66 individuals, PP1_Strong ( PMID: 8012359, PMID:9106529, PMID:17710899 and others). A REVEL score > 0.85 supports pathogenicity,PP3_Moderate. Based on using Bayes to combine criteria this variant is assessed as Pathogenic, (PMID: 29300386). Criteria implemented: PS4, PS3_Moderate, PM1, PP1_Strong, PP3_Moderate, BS2_Moderate. (less)
|
|
|
Pathogenic
(Mar 15, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV000852200.1
First in ClinVar: Jun 09, 2014 Last updated: Jun 09, 2014 |
|
|
|
Pathogenic
(Jun 23, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Athena Diagnostics
Accession: SCV002770437.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
Comment:
This variant has been identified in multiple unrelated individuals with susceptibility to malignant hyperthermia (MHS) and associates with MHS in multiple families. This variant has … (more)
This variant has been identified in multiple unrelated individuals with susceptibility to malignant hyperthermia (MHS) and associates with MHS in multiple families. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In some published literature, this variant is referred to as G342R. Assessment of experimental evidence suggests this variant results in abnormal protein function. Variant increased sensitivity to RYR1 activators (PMID:26115329, 9334205, 12732639). (less)
|
|
|
Pathogenic
(Jan 13, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
RYR1-related disorder
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000777472.7
First in ClinVar: May 28, 2018 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 341 of the RYR1 protein (p.Gly341Arg). … (more)
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 341 of the RYR1 protein (p.Gly341Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with malignant hyperthermia (PMID: 8012359, 8825043, 19648156, 24433488). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12969). 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. Experimental studies have shown that this missense change affects RYR1 function (PMID: 9334205, 9873004, 12732639). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Nov 05, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Malignant hyperthermia, susceptibility to, 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Molecular Genetics, Royal Melbourne Hospital
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV004812872.1
First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024 |
Comment:
This sequence change in RYR1 is predicted to replace glycine with arginine at codon 341, p.(Gly341Arg). The glycine residue is highly conserved (100 vertebrates, UCSC), … (more)
This sequence change in RYR1 is predicted to replace glycine with arginine at codon 341, p.(Gly341Arg). The glycine residue is highly conserved (100 vertebrates, UCSC), and is located in exon 11 in the N-terminal region, amino acids 1-552, which is defined as a mutational hotspot. There is a large physicochemical difference between glycine and arginine. This variant is absent from the population database gnomAD v2.1 and v3.1. This variant has been reported in multiple families with malignant hyperthermia susceptibility (MHS) confirmed by in vitro contracture testing (IVCT) and/or a personal/family history of an anaesthetic reaction, and it segregates with MHS in multiple families (PMID: 30236257). This variant has been observed in at least one family with a negative IVCT (PMID: 30236257). The variant demonstrates significantly enhanced sensitivity to calcium release in HEK293 cells indicating that this variant impacts protein function (PMID: 9334205, 26115329). Computational evidence predicts a deleterious effect for the missense substitution (REVEL = 0.864). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: PS4, PP1_Strong, PM1, PP3_Moderate, PS3_Moderate, BS2_Moderate. (less)
|
|
|
Pathogenic
(May 26, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV005324903.1
First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024 |
Comment:
Published functional studies suggest that the variant increases RYR1 channel sensitivity to caffeine and halothane and resistance to channel inactivation (PMID: 12732639, 9334205); In silico … (more)
Published functional studies suggest that the variant increases RYR1 channel sensitivity to caffeine and halothane and resistance to channel inactivation (PMID: 12732639, 9334205); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 19648156, 29101530, 9334205, 9873004, 30236257, 12124989, 31206373, 8825043, 35428369, 12732639, 8012359, 33057194, 26115329, 35982159) (less)
|
|
|
Likely pathogenic
(Sep 05, 2014)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000225241.5
First in ClinVar: Jun 28, 2015 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 1
Sex: mixed
|
|
|
Pathogenic
(May 06, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002019916.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Apr 18, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Malignant hyperthermia, susceptibility to, 1
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV004357272.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces glycine with arginine at codon 341 of the RYR1 protein. Computational prediction suggests that this variant may have deleterious impact on … (more)
This missense variant replaces glycine with arginine at codon 341 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 using HEK293 cells and dyspedic myotubes have shown this variant increases sensitivity to RYR1 agonists compared to wild type RYR1 (PMID: 9334205, 9873004, 12732639, 26115329). This variant has been reported in over 50 families and/or individuals affected with malignant hyperthermia (PMID: 8825043, 9106529, 16163667, 18564801, 19648156, 24433488, 30236257). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. (less)
|
|
|
Pathogenic
(Aug 15, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Malignant hyperthermia, susceptibility to, 1
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
All of Us Research Program, National Institutes of Health
Accession: SCV004820735.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024
Comment:
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more)
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)
|
Comment:
This missense variant replaces glycine with arginine at codon 341 of the RYR1 protein. Computational prediction suggests that this variant may have deleterious impact on … (more)
This missense variant replaces glycine with arginine at codon 341 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 using HEK293 cells and dyspedic myotubes have shown this variant increases sensitivity to RYR1 agonists compared to wild type RYR1 (PMID: 9334205, 9873004, 12732639, 26115329). This variant has been reported in over 50 families and/or individuals affected with malignant hyperthermia (PMID: 8825043, 9106529, 16163667, 18564801, 19648156, 24433488, 30236257). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. (less)
Number of individuals with the variant: 1
|
|
|
risk factor
(Oct 01, 1998)
|
no assertion criteria provided
Method: literature only
|
MALIGNANT HYPERTHERMIA, SUSCEPTIBILITY TO, 1
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000034083.4
First in ClinVar: Apr 04, 2013 Last updated: Jun 09, 2024 |
Comment on evidence:
In affected individuals from 3 unrelated families with malignant hyperthermia susceptibility (MHS1; 145600), Quane et al. (1994) identified a heterozygous c.1021G-A transition in the RYR1 … (more)
In affected individuals from 3 unrelated families with malignant hyperthermia susceptibility (MHS1; 145600), Quane et al. (1994) identified a heterozygous c.1021G-A transition in the RYR1 gene, resulting in a gly341-to-arg (G341R) substitution. The authors suggested that the G341R mutation may be responsible for approximately 10% of all MHS cases in Caucasians. However, Fagerlund et al. (1996) discovered this mutation in only 1 of 89 Swedish and Danish families with MHS. Alestrom et al. (1995) used the amplification-created restriction sites (ACRS) technique to detect the G341R mutation. The method discriminated quickly and efficiently between homozygotes with the mutation, heterozygotes, and homozygotes without the mutation. Adeokun et al. (1997) reported a large family in which the G341R mutation did not show complete cosegregation with MHS: it occurred in only 7 of 12 individuals in the kinship demonstrated to be MH sensitive by in vitro contracture tests (IVCTs), and susceptibility was inherited from parents who were homozygous wildtype c.1021G, as well as from parents who were heterozygotes. Monsieurs et al. (1998) found that 9 of 13 carriers of the G341R mutation in 2 families had elevated serum creatine kinase levels (up to 6 times the upper limit of normal). All had normal neurologic exams and muscle histology. The third family did not show increased creatine kinase levels. The authors suggested that the G341R mutation may be a cause of chronic elevation of serum creatine kinase in asymptomatic individuals. Whereas the G341R mutation is a frequent cause of malignant hyperthermia in European populations, Stewart et al. (1998) did not find the mutation in 114 North American individuals screened because of a family history or personal history of malignant hyperthermia. (less)
|
|
|
not provided
(-)
|
no classification provided
Method: not provided
|
not provided
Affected status: not provided
Allele origin:
unknown
|
Leiden Muscular Dystrophy (RYR1)
Accession: SCV000154313.1
First in ClinVar: Jun 09, 2014 Last updated: Jun 09, 2014
Comment:
rs28933997
|
|
|
| click to load more click to collapse | |||||
Comment:
Comment:
This variant has been identified in multiple unrelated individuals with susceptibility to malignant hyperthermia (MHS) and associates with MHS in multiple families. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In some published literature, this variant is referred to as G342R. Assessment of experimental evidence suggests this variant results in abnormal protein function. Variant increased sensitivity to RYR1 activators (PMID:26115329, 9334205, 12732639).
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 341 of the RYR1 protein (p.Gly341Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with malignant hyperthermia (PMID: 8012359, 8825043, 19648156, 24433488). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12969). 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. Experimental studies have shown that this missense change affects RYR1 function (PMID: 9334205, 9873004, 12732639). For these reasons, this variant has been classified as Pathogenic.
Comment:
This sequence change in RYR1 is predicted to replace glycine with arginine at codon 341, p.(Gly341Arg). The glycine residue is highly conserved (100 vertebrates, UCSC), and is located in exon 11 in the N-terminal region, amino acids 1-552, which is defined as a mutational hotspot. There is a large physicochemical difference between glycine and arginine. This variant is absent from the population database gnomAD v2.1 and v3.1. This variant has been reported in multiple families with malignant hyperthermia susceptibility (MHS) confirmed by in vitro contracture testing (IVCT) and/or a personal/family history of an anaesthetic reaction, and it segregates with MHS in multiple families (PMID: 30236257). This variant has been observed in at least one family with a negative IVCT (PMID: 30236257). The variant demonstrates significantly enhanced sensitivity to calcium release in HEK293 cells indicating that this variant impacts protein function (PMID: 9334205, 26115329). Computational evidence predicts a deleterious effect for the missense substitution (REVEL = 0.864). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: PS4, PP1_Strong, PM1, PP3_Moderate, PS3_Moderate, BS2_Moderate.
Comment:
Published functional studies suggest that the variant increases RYR1 channel sensitivity to caffeine and halothane and resistance to channel inactivation (PMID: 12732639, 9334205); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 19648156, 29101530, 9334205, 9873004, 30236257, 12124989, 31206373, 8825043, 35428369, 12732639, 8012359, 33057194, 26115329, 35982159)
Comment:
This missense variant replaces glycine with arginine at codon 341 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 using HEK293 cells and dyspedic myotubes have shown this variant increases sensitivity to RYR1 agonists compared to wild type RYR1 (PMID: 9334205, 9873004, 12732639, 26115329). This variant has been reported in over 50 families and/or individuals affected with malignant hyperthermia (PMID: 8825043, 9106529, 16163667, 18564801, 19648156, 24433488, 30236257). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Comment:
This missense variant replaces glycine with arginine at codon 341 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 using HEK293 cells and dyspedic myotubes have shown this variant increases sensitivity to RYR1 agonists compared to wild type RYR1 (PMID: 9334205, 9873004, 12732639, 26115329). This variant has been reported in over 50 families and/or individuals affected with malignant hyperthermia (PMID: 8825043, 9106529, 16163667, 18564801, 19648156, 24433488, 30236257). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
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 341 of the RYR1 protein p.(Gly341Arg), c.1021G>A. This variant is not present in a large population database (gnomAD). This variant has been reported in 71 unrelated probands who have a personal or family history of a malignant hyperthermia reaction and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (when the proband was unavailable for testing a positive diagnostic test result in a mutation positive relative was counted), PS4 ( PMID:30236257, PMID:16163667, PMID: 8012359 and others). Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID:26115329). 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 66 individuals, PP1_Strong ( PMID: 8012359, PMID:9106529, PMID:17710899 and others). A REVEL score > 0.85 supports pathogenicity,PP3_Moderate. Based on using Bayes to combine criteria this variant is assessed as Pathogenic, (PMID: 29300386). Criteria implemented: PS4, PS3_Moderate, PM1, PP1_Strong, PP3_Moderate, BS2_Moderate.
Comment:
This variant has been identified in multiple unrelated individuals with susceptibility to malignant hyperthermia (MHS) and associates with MHS in multiple families. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In some published literature, this variant is referred to as G342R. Assessment of experimental evidence suggests this variant results in abnormal protein function. Variant increased sensitivity to RYR1 activators (PMID:26115329, 9334205, 12732639).
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 341 of the RYR1 protein (p.Gly341Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with malignant hyperthermia (PMID: 8012359, 8825043, 19648156, 24433488). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12969). 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. Experimental studies have shown that this missense change affects RYR1 function (PMID: 9334205, 9873004, 12732639). For these reasons, this variant has been classified as Pathogenic.
Comment:
This sequence change in RYR1 is predicted to replace glycine with arginine at codon 341, p.(Gly341Arg). The glycine residue is highly conserved (100 vertebrates, UCSC), and is located in exon 11 in the N-terminal region, amino acids 1-552, which is defined as a mutational hotspot. There is a large physicochemical difference between glycine and arginine. This variant is absent from the population database gnomAD v2.1 and v3.1. This variant has been reported in multiple families with malignant hyperthermia susceptibility (MHS) confirmed by in vitro contracture testing (IVCT) and/or a personal/family history of an anaesthetic reaction, and it segregates with MHS in multiple families (PMID: 30236257). This variant has been observed in at least one family with a negative IVCT (PMID: 30236257). The variant demonstrates significantly enhanced sensitivity to calcium release in HEK293 cells indicating that this variant impacts protein function (PMID: 9334205, 26115329). Computational evidence predicts a deleterious effect for the missense substitution (REVEL = 0.864). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: PS4, PP1_Strong, PM1, PP3_Moderate, PS3_Moderate, BS2_Moderate.
Comment:
Published functional studies suggest that the variant increases RYR1 channel sensitivity to caffeine and halothane and resistance to channel inactivation (PMID: 12732639, 9334205); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 19648156, 29101530, 9334205, 9873004, 30236257, 12124989, 31206373, 8825043, 35428369, 12732639, 8012359, 33057194, 26115329, 35982159)
Comment:
This missense variant replaces glycine with arginine at codon 341 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 using HEK293 cells and dyspedic myotubes have shown this variant increases sensitivity to RYR1 agonists compared to wild type RYR1 (PMID: 9334205, 9873004, 12732639, 26115329). This variant has been reported in over 50 families and/or individuals affected with malignant hyperthermia (PMID: 8825043, 9106529, 16163667, 18564801, 19648156, 24433488, 30236257). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Comment:
This missense variant replaces glycine with arginine at codon 341 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 using HEK293 cells and dyspedic myotubes have shown this variant increases sensitivity to RYR1 agonists compared to wild type RYR1 (PMID: 9334205, 9873004, 12732639, 26115329). This variant has been reported in over 50 families and/or individuals affected with malignant hyperthermia (PMID: 8825043, 9106529, 16163667, 18564801, 19648156, 24433488, 30236257). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Expanding the clinical-pathological and genetic spectrum of RYR1-related congenital myopathies with cores and minicores: an Italian population study. | Fusto A | Acta neuropathologica communications | 2022 | PMID: 35428369 |
| BMI and malignant hyperthermia pathogenic ryanodine receptor type 1 sequence variants in Switzerland: A retrospective cohort analysis. | Gonzalez A | European journal of anaesthesiology | 2021 | PMID: 33259453 |
| Estimating prevalence of malignant hyperthermia susceptibility through population genomics data. | Mungunsukh O | British journal of anaesthesia | 2019 | PMID: 31301762 |
| An Assessment of Penetrance and Clinical Expression of Malignant Hyperthermia in Individuals Carrying Diagnostic Ryanodine Receptor 1 Gene Mutations. | Ibarra Moreno CA | Anesthesiology | 2019 | PMID: 31206373 |
| Genetic epidemiology of malignant hyperthermia in the UK. | Miller DM | British journal of anaesthesia | 2018 | PMID: 30236257 |
| Divergent Activity Profiles of Type 1 Ryanodine Receptor Channels Carrying Malignant Hyperthermia and Central Core Disease Mutations in the Amino-Terminal Region. | Murayama T | PloS one | 2015 | PMID: 26115329 |
| Functional and genetic characterization of clinical malignant hyperthermia crises: a multi-centre study. | Klingler W | Orphanet journal of rare diseases | 2014 | PMID: 24433488 |
| Genetic variation in RYR1 and malignant hyperthermia phenotypes. | Carpenter D | British journal of anaesthesia | 2009 | PMID: 19648156 |
| Identification of genetic mutations in Australian malignant hyperthermia families using sequencing of RYR1 hotspots. | Gillies RL | Anaesthesia and intensive care | 2008 | PMID: 18564801 |
| Mutations in RYR1 in malignant hyperthermia and central core disease. | Robinson R | Human mutation | 2006 | PMID: 16917943 |
| Correlations between genotype and pharmacological, histological, functional, and clinical phenotypes in malignant hyperthermia susceptibility. | Monnier N | Human mutation | 2005 | PMID: 16163667 |
| Functional defects in six ryanodine receptor isoform-1 (RyR1) mutations associated with malignant hyperthermia and their impact on skeletal excitation-contraction coupling. | Yang T | The Journal of biological chemistry | 2003 | PMID: 12732639 |
| Mutation screening in the ryanodine receptor 1 gene (RYR1) in patients susceptible to malignant hyperthermia who show definite IVCT results: identification of three novel mutations. | Rueffert H | Acta anaesthesiologica Scandinavica | 2002 | PMID: 12059893 |
| Measurement of resting cytosolic Ca2+ concentrations and Ca2+ store size in HEK-293 cells transfected with malignant hyperthermia or central core disease mutant Ca2+ release channels. | Tong J | The Journal of biological chemistry | 1999 | PMID: 9873004 |
| Failure to identify the ryanodine receptor G1021A mutation in a large North American population with malignant hyperthermia. | Stewart SL | Clinical genetics | 1998 | PMID: 9831351 |
| Gly341Arg mutation indicating malignant hyperthermia susceptibility: specific cause of chronically elevated serum creatine kinase activity. | Monsieurs KG | Journal of the neurological sciences | 1998 | PMID: 9543323 |
| Discordance between malignant hyperthermia susceptibility and RYR1 mutation C1840T in two Scandinavian MH families exhibiting this mutation. | Fagerlund TH | Clinical genetics | 1997 | PMID: 9520251 |
| Caffeine and halothane sensitivity of intracellular Ca2+ release is altered by 15 calcium release channel (ryanodine receptor) mutations associated with malignant hyperthermia and/or central core disease. | Tong J | The Journal of biological chemistry | 1997 | PMID: 9334205 |
| The G1021A substitution in the RYR1 gene does not cosegregate with malignant hyperthermia susceptibility in a British pedigree. | Adeokun AM | American journal of human genetics | 1997 | PMID: 9106529 |
| Diagnosis of malignant hyperthermia: a comparison of the in vitro contracture test with the molecular genetic diagnosis in a large pedigree. | Healy JM | Journal of medical genetics | 1996 | PMID: 8825043 |
| A simple method to detect the RYR1 mutation G1021A, a cause of malignant hyperthermia susceptibility. | Alestrøm A | Clinical genetics | 1995 | PMID: 7554356 |
| Detection of a novel common mutation in the ryanodine receptor gene in malignant hyperthermia: implications for diagnosis and heterogeneity studies. | Quane KA | Human molecular genetics | 1994 | PMID: 8012359 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=RYR1 | - | - | - | - |
| https://erepo.clinicalgenome.org/evrepo/ui/interpretation/9fd209aa-12fb-400e-9b0f-37a7981de6b7 | - | - | - | - |
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Text-mined citations for rs121918592 ...
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Record last updated Nov 25, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.