NM_000540.3(RYR1):c.1021G>A (p.Gly341Arg) AND not provided

Germline classification:: Pathogenic/Likely pathogenic (7 submissions)
Last evaluated:: Nov 25, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000119406.28

Allele description [Variation Report for NM_000540.3(RYR1):c.1021G>A (p.Gly341Arg)]

NM_000540.3(RYR1):c.1021G>A (p.Gly341Arg)

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.1021G>A (p.Gly341Arg)

Other names:

NM_000540.3(RYR1):c.1021G>A

HGVS:

NC_000019.10:g.38448712G>A
NG_008866.1:g.20013G>A
NM_000540.3:c.1021G>AMANE SELECT
NM_001042723.2:c.1021G>A
NP_000531.2:p.Gly341Arg
NP_000531.2:p.Gly341Arg
NP_001036188.1:p.Gly341Arg
LRG_766t1:c.1021G>A
LRG_766:g.20013G>A
LRG_766p1:p.Gly341Arg
NC_000019.9:g.38939352G>A
NM_000540.2:c.1021G>A
P21817:p.Gly341Arg
p.(Gly341Arg)

Protein change:

G341R; GLY341ARG

Links:

UniProtKB: P21817#VAR_005592; OMIM: 180901.0006; dbSNP: rs121918592

NCBI 1000 Genomes Browser:

rs121918592

Molecular consequence:

NM_000540.3:c.1021G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001042723.2:c.1021G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided; RECLASSIFIED - ADRA2C POLYMORPHISM; RECLASSIFIED - ADRB1 POLYMORPHISM
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000154313	RYR1 database	no classification provided	not provided	unknown	not provided
SCV000225241	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions 2015)	Likely pathogenic (Sep 5, 2014)	germline	clinical testing	Citation Link,
SCV000852200	PreventionGenetics, part of Exact Sciences	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 15, 2018)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002019916	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 6, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002770437	Athena Diagnostics	criteria provided, single submitter (Athena Diagnostics Criteria)	Pathogenic (Jun 23, 2022)	unknown	clinical testing	PubMed (18) [See all records that cite these PMIDs] 31301762, 30236257, 35428369, 31206373, 33259453, 26115329, 24433488, 19648156, 18564801, 16917943, 12732639, 12059893, 9873004, 9831351, 9334205, 8825043, 8012359, 26467025
SCV005324903	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (May 26, 2022)	germline	clinical testing	Citation Link,
SCV005876145	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024)	Pathogenic (Nov 25, 2024)	germline	clinical testing	Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	not provided	not provided	not provided	not provided	1	not provided	literature only
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee.

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Estimating prevalence of malignant hyperthermia susceptibility through population genomics data.

Mungunsukh O, Deuster P, Muldoon S, O'Connor F, Sambuughin N.

Br J Anaesth. 2019 Sep;123(3):e461-e463. doi: 10.1016/j.bja.2019.06.010. Epub 2019 Jul 10. No abstract available.

PubMed [citation]

PMID:: 31301762

See all PubMed Citations (19)

Details of each submission

From RYR1 database, SCV000154313.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	not provided	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	not provided	1	not provided	not provided		not provided	not provided	not provided	not provided

From Eurofins Ntd Llc (ga), SCV000225241.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	not provided

#	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		1	not provided	not provided	not provided

From PreventionGenetics, part of Exact Sciences, SCV000852200.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	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	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Revvity Omics, Revvity, SCV002019916.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	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	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Athena Diagnostics, SCV002770437.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (18)

Description

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).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From GeneDx, SCV005324903.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

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)

#	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		not provided	not provided	not provided	not provided

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV005876145.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

The RYR1 c.1021G>A; p.Gly341Arg variant (rs121918592) is reported in the literature in numerous individuals affected with malignant hyperthermia and has been shown to segregate with disease in multiple large kindreds (Healy 1996, Heytens 2007, Miller 2018, Monnier 2005). This variant is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.864), and functional analyses in cultured cells indicate increased sensitivity to RYR1 agonists (Tong 1997). Based on available information, this variant is considered to be pathogenic. References: Healy JM et al. Diagnosis of malignant hyperthermia: a comparison of the in vitro contracture test with the molecular genetic diagnosis in a large pedigree. J Med Genet. 1996 Jan;33(1):18-24. PMID: 8825043. Heytens L. Molecular genetic detection of susceptibility to malignant hyperthermia in Belgian families. Acta Anaesthesiol Belg. 2007;58(2):113-8. PMID: 17710899. Miller DM et al. Genetic epidemiology of malignant hyperthermia in the UK. Br J Anaesth. 2018 Oct;121(4):944-952. PMID: 30236257. Monnier N et al. Correlations between genotype and pharmacological, histological, functional, and clinical phenotypes in malignant hyperthermia susceptibility. Hum Mutat. 2005 Nov;26(5):413-25. PMID: 16163667. Tong J et al. 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. J Biol Chem. 1997 Oct 17;272(42):26332-9. PMID: 9334205.

#	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

Last Updated: May 16, 2025

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