NM_000540.3(RYR1):c.8327C>T (p.Ser2776Phe) AND Malignant hyperthermia, susceptibility to, 1

Germline classification:: Likely benign (6 submissions)
Last evaluated:: Mar 18, 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:: RCV000210026.13

Allele description [Variation Report for NM_000540.3(RYR1):c.8327C>T (p.Ser2776Phe)]

NM_000540.3(RYR1):c.8327C>T (p.Ser2776Phe)

Genes:

LOC126862902:BRD4-independent group 4 enhancer GRCh37_chr19:38995830-38997029 [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.8327C>T (p.Ser2776Phe)

HGVS:

NC_000019.10:g.38505325C>T
NG_008866.1:g.76626C>T
NM_000540.3:c.8327C>TMANE SELECT
NM_001042723.2:c.8327C>T
NP_000531.2:p.Ser2776Phe
NP_000531.2:p.Ser2776Phe
NP_001036188.1:p.Ser2776Phe
LRG_766t1:c.8327C>T
LRG_766:g.76626C>T
LRG_766p1:p.Ser2776Phe
NC_000019.9:g.38995965C>T
NM_000540.2:c.8327C>T
NM_000540.3(RYR1):c.8327C>TMANE SELECT

Protein change:

S2776F

Links:

dbSNP: rs147707463

NCBI 1000 Genomes Browser:

rs147707463

Molecular consequence:

NM_000540.3:c.8327C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001042723.2:c.8327C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

314

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
SCV000265728	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]
SCV000412558	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Likely benign (Apr 27, 2017)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 21514828, 21965348, 22705209 Citation Link,
SCV001810087	ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen	reviewed by expert panel (ClinGen MHS ACMG Specifications V1)	Likely benign (Mar 18, 2021)	germline	curation	Citation Link,
SCV004358149	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely benign (Jul 19, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004812398	Molecular Genetics, Royal Melbourne Hospital See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely benign (May 4, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005425137	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely Benign (Sep 23, 2024)	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	unknown	unknown	1	not provided	not provided	not provided	not provided	research
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	314	not provided	not provided	143475	not provided	clinical testing, curation

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

King-Denborough syndrome with and without mutations in the skeletal muscle ryanodine receptor (RYR1) gene.

Dowling JJ, Lillis S, Amburgey K, Zhou H, Al-Sarraj S, Buk SJ, Wraige E, Chow G, Abbs S, Leber S, Lachlan K, Baralle D, Taylor A, Sewry C, Muntoni F, Jungbluth H.

Neuromuscul Disord. 2011 Jun;21(6):420-7. doi: 10.1016/j.nmd.2011.03.006. Epub 2011 Apr 22.

PubMed [citation]

PMID:: 21514828

See all PubMed Citations (5)

Details of each submission

From Biesecker Lab/Clinical Genomics Section, National Institutes of Health - ClinSeq, SCV000265728.1

#	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 Illumina Laboratory Services, Illumina, SCV000412558.3

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

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, SCV001810087.1

#	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 2776 of the RYR1 protein p.(Ser2776Phe). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.00145, this is considered to be more common than expected for a pathogenic variant causing autosomal dominant MHS, BS1. This variant has been reported in two unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, both of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (when the proband was unavailable for testing a positive diagnostic test result in a mutation positive relative was counted), ( PMID:21965348, PMID:30236257 ). However, the high MAF in the NFE population in gnomAD precludes the use of PS4. 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 of 0.693 does not support a pathogenic or a benign status. This variant has been classified as Likely Benign. Criteria implemented: BS1.

#	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, SCV004358149.2

#	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

From Molecular Genetics, Royal Melbourne Hospital, SCV004812398.1

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

Description

European Non-Finnish population allele frequency is 0.1329%% (rs147707463, 186/128,314 alleles, 0 homozygotes in gnomAD v2.1). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.5.1, this variant is classified as LIKELY BENIGN. Following criteria are met: BS1

#	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 All of Us Research Program, National Institutes of Health, SCV005425137.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	314	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	143475	not provided	not provided		314	not provided	not provided	not provided

Last Updated: Jun 22, 2025

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