NM_000540.3(RYR1):c.5183C>T (p.Ser1728Phe) AND Malignant hyperthermia, susceptibility to, 1

Germline classification:: Likely pathogenic (6 submissions)
Last evaluated:: May 20, 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:: RCV000148807.9

Allele description [Variation Report for NM_000540.3(RYR1):c.5183C>T (p.Ser1728Phe)]

NM_000540.3(RYR1):c.5183C>T (p.Ser1728Phe)

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.5183C>T (p.Ser1728Phe)

Other names:

NM_000540.2(RYR1):c.5183C>T

HGVS:

NC_000019.10:g.38485838C>T
NG_008866.1:g.57139C>T
NM_000540.3:c.5183C>TMANE SELECT
NM_001042723.2:c.5183C>T
NP_000531.2:p.Ser1728Phe
NP_000531.2:p.Ser1728Phe
NP_001036188.1:p.Ser1728Phe
LRG_766t1:c.5183C>T
LRG_766:g.57139C>T
LRG_766p1:p.Ser1728Phe
NC_000019.9:g.38976478C>T
NM_000540.2:c.5183C>T
NM_000540.3:c.5183C>T

Protein change:

S1728F

Links:

dbSNP: rs193922781

NCBI 1000 Genomes Browser:

rs193922781

Molecular consequence:

NM_000540.3:c.5183C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001042723.2:c.5183C>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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000190546	CSER _CC_NCGL, University of Washington - ESP 6500 variant annotation	no assertion criteria provided	Pathogenic (Jun 1, 2014)	germline	research
SCV000265707	Biesecker Lab/Clinical Genomics Section, National Institutes of Health - ClinSeq	criteria provided, single submitter (Gonsalves et al. 2013)	Pathogenic (Jul 1, 2013)	unknown	research	PubMed (1) [See all records that cite this PMID]
SCV001439388	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology - CSER-SouthSeq	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Sep 3, 2020)	maternal	research	PubMed (1) [See all records that cite this PMID]
SCV002522189	National Institute of Allergy and Infectious Diseases - Centralized Sequencing Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 6, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003930277	ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen	reviewed by expert panel (ClinGen MHS ACMG Specifications V2)	Likely pathogenic (May 20, 2023)	germline	curation	Citation Link,
SCV004046154	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic	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	no	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	maternal	unknown	1	not provided	not provided	1	not provided	research
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	research, curation
not provided	unknown	unknown	1	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

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 CSER _CC_NCGL, University of Washington - ESP 6500 variant annotation, SCV000190546.1

#	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 Biesecker Lab/Clinical Genomics Section, National Institutes of Health - ClinSeq, SCV000265707.1

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

From HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology - CSER-SouthSeq, SCV001439388.1

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

Description

ACMG codes:PS4, PM2, PP3, PP5

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

From National Institute of Allergy and Infectious Diseases - Centralized Sequencing Program, National Institutes of Health, SCV002522189.1

#	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	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen, SCV003930277.1

#	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 Serine with Phenylalanine at codon 1728 of the RYR1 protein, p.(Ser1728Phe). The maximum allele frequency for this variant among the six major gnomAD populations is AMR: MAF 0.000029, a frequency consistent with pathogenicity for MHS. This variant has been reported in nine unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, nine 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 (PMID:30236257; PMID:15731587). This variant segregates with MHS in five families, PP1_Strong (PMID:30236257). No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score <0.5 supports a benign status for this variant, BP4. Based on using Bayes to combine criteria this variant is assessed as Likely Pathogenic, (PMID: 29300386). Criteria implemented: PS4, PP1_Strong, BP4.

#	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 Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego, SCV004046154.1

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

Description

This variant has been previously reported as a heterozygous change in patients with malignant hyperthermia (MH) susceptibility (PMID: 19648156, 30236257). In vitro contracture tests have shown this variant may be associated with a weaker MH phenotype (PMID: 19648156). The c.5183C>T (p.Ser1728Phe) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.0004% (1/246040) and is absent in the homozygous state, thus is presumed to be rare. The c.5183C>T (p.Ser1728Phe) variant affects a moderately conserved amino acid; however, in silico tools used to predict the effect of this variant on protein function yield discordant results. Based on the available evidence, the c.5183C>T (p.Ser1728Phe) variant is classified as Likely Pathogenic.

#	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

Last Updated: Nov 3, 2024

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