NM_000540.3(RYR1):c.7204C>T (p.Arg2402Trp) AND Malignant hyperthermia, susceptibility to, 1

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Dec 1, 2023
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:: RCV002225094.5

Allele description [Variation Report for NM_000540.3(RYR1):c.7204C>T (p.Arg2402Trp)]

NM_000540.3(RYR1):c.7204C>T (p.Arg2402Trp)

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.7204C>T (p.Arg2402Trp)

Other names:

p.Arg2402Trp

HGVS:

NC_000019.10:g.38499811C>T
NG_008866.1:g.71112C>T
NM_000540.3:c.7204C>TMANE SELECT
NM_001042723.2:c.7204C>T
NP_000531.2:p.Arg2402Trp
NP_000531.2:p.Arg2402Trp
NP_001036188.1:p.Arg2402Trp
LRG_766t1:c.7204C>T
LRG_766:g.71112C>T
LRG_766p1:p.Arg2402Trp
NC_000019.9:g.38990451C>T
NM_000540.2:c.7204C>T

Protein change:

R2402W

Links:

dbSNP: rs575780192

NCBI 1000 Genomes Browser:

rs575780192

Molecular consequence:

NM_000540.3:c.7204C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001042723.2:c.7204C>T - 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
SCV002503747	Molecular Genetics, Royal Melbourne Hospital See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Mar 30, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004820905	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Dec 1, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002503747

Molecular Genetics, Royal Melbourne Hospital

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Mar 30, 2023)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV004820905

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Dec 1, 2023)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

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	germline	unknown	9	not provided	not provided	108544	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

Details of each submission

From Molecular Genetics, Royal Melbourne Hospital, SCV002503747.2

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

Description

This sequence change is predicted to replace arginine with tryptophan at codon 2402 in exon 44 of the RYR1 protein (p.(Arg2402Trp)). The arginine residue is moderately conserved (100 vertebrates, UCSC), and is located in the RYR1 cytosolic shell. There is a large physicochemical difference between arginine and tryptophan. The variant is present in a large population cohort at a frequency of 0.01% (rs575780192, 34/266,730 alleles, 0 homozygotes in gnomAD v2.1), with a frequency of 0.1% in the east Asian population (25/19,482 alleles in gnomAD v2.1). The variant has been not been reported in RYR1-related disorders in the relevant medical literature, and has been reported as a variant of uncertain significance (ClinVar). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (4/4 algorithms). Based on the classification scheme RMH Modified ACMG Guidelines v1.3.1, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: PP3.

#	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 All of Us Research Program, National Institutes of Health, SCV004820905.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	9	not provided	not provided	clinical testing	PubMed (1)

Description

This missense variant replaces arginine with tryptophan at codon 2402 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 not been reported in individuals affected with RYR1-related disorders in the literature. This variant has been identified in 34/266730 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		9	not provided	not provided	not provided

Last Updated: Sep 29, 2024

ClinVar

Relating variation to medicine