NM_000540.3(RYR1):c.4999C>T (p.Arg1667Cys) AND Malignant hyperthermia, susceptibility to, 1

Germline classification:: Benign (4 submissions)
Last evaluated:: Mar 17, 2021
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:: RCV000210024.10

Allele description [Variation Report for NM_000540.3(RYR1):c.4999C>T (p.Arg1667Cys)]

NM_000540.3(RYR1):c.4999C>T (p.Arg1667Cys)

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.4999C>T (p.Arg1667Cys)

Other names:

NM_000540.2(RYR1):c.4999C>T

HGVS:

NC_000019.10:g.38485654C>T
NG_008866.1:g.56955C>T
NM_000540.3:c.4999C>TMANE SELECT
NM_001042723.2:c.4999C>T
NP_000531.2:p.Arg1667Cys
NP_000531.2:p.Arg1667Cys
NP_001036188.1:p.Arg1667Cys
LRG_766t1:c.4999C>T
LRG_766:g.56955C>T
LRG_766p1:p.Arg1667Cys
NC_000019.9:g.38976294C>T
NM_000540.2:c.4999C>T

Protein change:

R1667C

Links:

dbSNP: rs144157950

NCBI 1000 Genomes Browser:

rs144157950

Molecular consequence:

NM_000540.3:c.4999C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001042723.2:c.4999C>T - missense variant - [Sequence Ontology: SO:0001583]

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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Aphanomyces astaci threonine-tRNA ligase mRNA
Aphanomyces astaci threonine-tRNA ligase mRNA
gi|698794861|ref|XM_009832158.1||gn _WGS:AYTG|mrna_H257_06793T0

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000265705	Biesecker Lab/Clinical Genomics Section, National Institutes of Health - ClinSeq	criteria provided, single submitter (Gonsalves et al. 2013)	Likely benign (Jul 1, 2013)	unknown	research	PubMed (1) [See all records that cite this PMID]
SCV000412220	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Likely benign (Nov 5, 2018)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 21455645, 16732084 Citation Link,
SCV001816190	ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen - ClinGen	reviewed by expert panel (ClinGen MHS ACMG Specifications V1)	Benign (Mar 17, 2021)	germline	curation	Citation Link,
SCV004358079	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely benign (Mar 29, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

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Summary from all submissions

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

Citations

PubMed

Using exome data to identify malignant hyperthermia susceptibility mutations.

Gonsalves SG, Ng D, Johnston JJ, Teer JK, Stenson PD, Cooper DN, Mullikin JC, Biesecker LG; NISC Comparative Sequencing Program..

Anesthesiology. 2013 Nov;119(5):1043-53. doi: 10.1097/ALN.0b013e3182a8a8e7.

PubMed [citation]

PMID:: 24195946
PMCID:: PMC4077354

Ryanodine receptor type 1 gene mutations found in the Canadian malignant hyperthermia population.

Kraeva N, Riazi S, Loke J, Frodis W, Crossan ML, Nolan K, Kraev A, Maclennan DH.

Can J Anaesth. 2011 Jun;58(6):504-13. doi: 10.1007/s12630-011-9494-6. Epub 2011 Mar 31.

PubMed [citation]

PMID:: 21455645

See all PubMed Citations (4)

Details of each submission

From Biesecker Lab/Clinical Genomics Section, National Institutes of Health - ClinSeq, SCV000265705.1

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

#	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		5	not provided	not provided	not provided

From Illumina Laboratory Services, Illumina, SCV000412220.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

#	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 - ClinGen, SCV001816190.1

#	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 Arginine with Cysteine at codon 1667 of the RYR1 protein, p.(Arg1667Cys). The maximum allele frequency for this variant among the six major gnomAD populations is EAS: 0.0051, which is considered to be too common for a pathogenic variant causing autosomal dominantly inherited MHS, BA1. This variant has been classified as Benign. Criteria implemented: BA1.

#	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, SCV004358079.1

#	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

Last Updated: Oct 8, 2024

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