NM_000540.3(RYR1):c.668A>G (p.His223Arg) AND Malignant hyperthermia, susceptibility to, 1

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Dec 18, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV004004442.2

Allele description [Variation Report for NM_000540.3(RYR1):c.668A>G (p.His223Arg)]

NM_000540.3(RYR1):c.668A>G (p.His223Arg)

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.668A>G (p.His223Arg)

HGVS:

NC_000019.10:g.38446508A>G
NG_008866.1:g.17809A>G
NM_000540.3:c.668A>GMANE SELECT
NM_001042723.2:c.668A>G
NP_000531.2:p.His223Arg
NP_001036188.1:p.His223Arg
LRG_766t1:c.668A>G
LRG_766:g.17809A>G
NC_000019.9:g.38937148A>G
NM_000540.2:c.668A>G

Protein change:

H223R

Links:

dbSNP: rs766836202

NCBI 1000 Genomes Browser:

rs766836202

Molecular consequence:

NM_000540.3:c.668A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001042723.2:c.668A>G - 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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MGAM [Mandrillus leucophaeus]
MGAM [Mandrillus leucophaeus]
Gene ID:105550543

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004815853	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Dec 18, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 21118704, 33037202, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004815853

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Dec 18, 2023)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	5	not provided	not provided	108544	not provided	clinical testing

Citations

PubMed

Mechanistic models for muscle diseases and disorders originating in the sarcoplasmic reticulum.

Maclennan DH, Zvaritch E.

Biochim Biophys Acta. 2011 May;1813(5):948-64. doi: 10.1016/j.bbamcr.2010.11.009. Epub 2010 Nov 27. Review.

PubMed [citation]

PMID:: 21118704

Adaptive thermogenesis enhances the life-threatening response to heat in mice with an Ryr1 mutation.

Wang HJ, Lee CS, Yee RSZ, Groom L, Friedman I, Babcock L, Georgiou DK, Hong J, Hanna AD, Recio J, Choi JM, Chang T, Agha NH, Romero J, Sarkar P, Voermans N, Gaber MW, Jung SY, Baker ML, Pautler RG, Dirksen RT, Riazi S, et al.

Nat Commun. 2020 Oct 9;11(1):5099. doi: 10.1038/s41467-020-18865-z.

PubMed [citation]

PMID:: 33037202
PMCID:: PMC7547078

See all PubMed Citations (3)

Details of each submission

From All of Us Research Program, National Institutes of Health, SCV004815853.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	5	not provided	not provided	clinical testing	PubMed (3)

Description

This missense variant replaces histidine with arginine at codon 223 of the RYR1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.85, PMID: 27666373). his variant occurs in the N-terminal region (a.a. 1-552) of the RYR1 protein that is considered to be a hotspot for pathogenic variants that contribute to malignant hyperthermia susceptibility (PMID: 21118704). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with autosomal dominant malignant hyperthermia in the literature, although it has been reported in individuals with other phenotype(s) (Clinvar Variation ID: 808528; PMID: 33037202). This variant has been identified in 4/282866 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Due to insufficient evidence, this variant is classified as a Variant of Uncertain Significance for autosomal dominant malignant hyperthermia.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	108544	not provided	not provided		5	not provided	not provided	not provided

Last Updated: Oct 20, 2024

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