NM_000540.3(RYR1):c.7072A>C (p.Ile2358Leu) AND Malignant hyperthermia, susceptibility to, 1

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Nov 30, 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:: RCV003999857.2

Allele description [Variation Report for NM_000540.3(RYR1):c.7072A>C (p.Ile2358Leu)]

NM_000540.3(RYR1):c.7072A>C (p.Ile2358Leu)

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.7072A>C (p.Ile2358Leu)

HGVS:

NC_000019.10:g.38499679A>C
NG_008866.1:g.70980A>C
NM_000540.3:c.7072A>CMANE SELECT
NM_001042723.2:c.7072A>C
NP_000531.2:p.Ile2358Leu
NP_000531.2:p.Ile2358Leu
NP_001036188.1:p.Ile2358Leu
LRG_766t1:c.7072A>C
LRG_766:g.70980A>C
LRG_766p1:p.Ile2358Leu
NC_000019.9:g.38990319A>C
NM_000540.2:c.7072A>C

Protein change:

I2358L

Links:

dbSNP: rs759306349

NCBI 1000 Genomes Browser:

rs759306349

Molecular consequence:

NM_000540.3:c.7072A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001042723.2:c.7072A>C - 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
SCV004820899	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Nov 30, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 23558838, 31559918, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004820899

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Nov 30, 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

Ryanodine receptor type 1 gene variants in the malignant hyperthermia-susceptible population of the United States.

Brandom BW, Bina S, Wong CA, Wallace T, Visoiu M, Isackson PJ, Vladutiu GD, Sambuughin N, Muldoon SM.

Anesth Analg. 2013 May;116(5):1078-1086. doi: 10.1213/ANE.0b013e31828a71ff. Epub 2013 Apr 4.

PubMed [citation]

PMID:: 23558838
PMCID:: PMC3633164

Bayesian modeling to predict malignant hyperthermia susceptibility and pathogenicity of RYR1, CACNA1S and STAC3 variants.

Sadhasivam S, Brandom BW, Henker RA, McAuliffe JJ.

Pharmacogenomics. 2019 Sep;20(14):989-1003. doi: 10.2217/pgs-2019-0055.

PubMed [citation]

PMID:: 31559918
PMCID:: PMC7006767

See all PubMed Citations (3)

Details of each submission

From All of Us Research Program, National Institutes of Health, SCV004820899.1

#	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 isoleucine with leucine at codon 2358 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual with malignant hyperthermia susceptibility (PMID: 23558838, 31559918). This variant has been identified in 1/239514 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

#	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: Sep 29, 2024

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