NM_000540.3(RYR1):c.7291G>A (p.Asp2431Asn) AND Malignant hyperthermia, susceptibility to, 1

Germline classification:: Likely pathogenic (4 submissions)
Last evaluated:: Apr 7, 2023
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

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:: RCV000148824.7

Allele description [Variation Report for NM_000540.3(RYR1):c.7291G>A (p.Asp2431Asn)]

NM_000540.3(RYR1):c.7291G>A (p.Asp2431Asn)

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.7291G>A (p.Asp2431Asn)

Other names:

NM_000540.2(RYR1):c.7291G>A

HGVS:

NC_000019.10:g.38499984G>A
NG_008866.1:g.71285G>A
NM_000540.3:c.7291G>AMANE SELECT
NM_001042723.2:c.7291G>A
NP_000531.2:p.Asp2431Asn
NP_000531.2:p.Asp2431Asn
NP_001036188.1:p.Asp2431Asn
LRG_766t1:c.7291G>A
LRG_766:g.71285G>A
LRG_766p1:p.Asp2431Asn
NC_000019.9:g.38990624G>A
NC_000019.9:g.38990624G>A
NM_000540.2:c.7291G>A
P21817:p.Asp2431Asn
p.(Asp2431Asn)

Protein change:

D2431N

Links:

UniProtKB: P21817#VAR_045726; dbSNP: rs193922810

NCBI 1000 Genomes Browser:

rs193922810

Molecular consequence:

NM_000540.3:c.7291G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001042723.2:c.7291G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000190563	CSER _CC_NCGL, University of Washington - ESP 6500 variant annotation	no assertion criteria provided	Uncertain significance (Jun 1, 2014)	germline	research
SCV002047607	ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen	reviewed by expert panel (RYR1-MHS Interpretation Guidelines V2)	Likely pathogenic (Apr 7, 2023)	germline	curation	Citation Link,
SCV004358125	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Apr 27, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 11575529, 12411786, 15448513, 21118704, 30236257, 25741868
SCV004829333	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely Pathogenic (Nov 28, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 11575529, 12411786, 15448513, 21118704, 30236257, 25741868

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	4	not provided	not provided	108544	not provided	clinical testing, research, curation

Citations

PubMed

North American malignant hyperthermia population: screening of the ryanodine receptor gene and identification of novel mutations.

Sambuughin N, Sei Y, Gallagher KL, Wyre HW, Madsen D, Nelson TE, Fletcher JE, Rosenberg H, Muldoon SM.

Anesthesiology. 2001 Sep;95(3):594-9.

PubMed [citation]

PMID:: 11575529

Patients with malignant hyperthermia demonstrate an altered calcium control mechanism in B lymphocytes.

Sei Y, Brandom BW, Bina S, Hosoi E, Gallagher KL, Wyre HW, Pudimat PA, Holman SJ, Venzon DJ, Daly JW, Muldoon S.

Anesthesiology. 2002 Nov;97(5):1052-8.

PubMed [citation]

PMID:: 12411786

See all PubMed Citations (6)

Details of each submission

From CSER _CC_NCGL, University of Washington - ESP 6500 variant annotation, SCV000190563.1

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

From ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen, SCV002047607.2

#	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 aspartic acid with asparagine at codon 2431 of the RYR1 protein, p.(Asp2431Asn). The maximum allele frequency for this variant among the six major gnomAD populations is AFR: 0.000062, a frequency consistent with pathogenicity for MHS. This variant has been reported in two unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, two 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_Moderate (PMID:11575529, PMID:30236257). No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). A REVEL score >0.85 (0.888) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as Likely Pathogenic. Criteria implemented: PS4_Moderate, PM1, PP3_Moderate.

#	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, SCV004358125.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This missense variant replaces aspartic acid with asparagine at codon 2431 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). Although functional studies have not been reported for this variant, it occurs in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to malignant hyperthermia susceptibility (PMID: 21118704). This variant has been reported in individuals and families affected with malignant hyperthermia susceptibility (PMID: 11575529, 12411786, 15448513, 30236257). This variant has been identified in 2/251290 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely 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, SCV004829333.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	4	not provided	not provided	clinical testing	PubMed (6)

Description

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	108544	not provided	not provided		4	not provided	not provided	not provided

Last Updated: Aug 25, 2024

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