NM_000540.3(RYR1):c.6478G>A (p.Gly2160Ser) AND Malignant hyperthermia, susceptibility to, 1

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Apr 6, 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:: RCV001124361.8

Allele description [Variation Report for NM_000540.3(RYR1):c.6478G>A (p.Gly2160Ser)]

NM_000540.3(RYR1):c.6478G>A (p.Gly2160Ser)

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.6478G>A (p.Gly2160Ser)

Other names:

NM_000540.2(RYR1):c.6478G>A; p.Gly2160Ser

HGVS:

NC_000019.10:g.38494555G>A
NG_008866.1:g.65856G>A
NM_000540.3:c.6478G>AMANE SELECT
NM_001042723.2:c.6478G>A
NP_000531.2:p.Gly2160Ser
NP_000531.2:p.Gly2160Ser
NP_001036188.1:p.Gly2160Ser
LRG_766t1:c.6478G>A
LRG_766:g.65856G>A
LRG_766p1:p.Gly2160Ser
NC_000019.9:g.38985195G>A
NM_000540.2:c.6478G>A

Protein change:

G2160S

Links:

dbSNP: rs143398211

NCBI 1000 Genomes Browser:

rs143398211

Molecular consequence:

NM_000540.3:c.6478G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001042723.2:c.6478G>A - 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
SCV001283308	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Uncertain significance (Apr 28, 2017)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 23476141, 26332594, 25637381, 19807743 Citation Link,
SCV001816185	ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen - ClinGen	reviewed by expert panel (RYR1-MHS Interpretation Guidelines V2)	Uncertain significance (Apr 6, 2023)	germline	curation	Citation Link,
SCV004820882	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Dec 13, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 30236257, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001283308

Illumina Laboratory Services, Illumina

criteria provided, single submitter

(ICSL Variant Classification Criteria 13 December 2019)

Uncertain significance
(Apr 28, 2017)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Citation Link,

SCV001816185

ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen - ClinGen

reviewed by expert panel

(RYR1-MHS Interpretation Guidelines V2)

Uncertain significance
(Apr 6, 2023)

germline

curation

Citation Link,

SCV004820882

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Dec 13, 2023)

germline

clinical testing

PubMed (2)
[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	7	not provided	not provided	108544	not provided	clinical testing, curation

Citations

PubMed

Exercise-induced rhabdomyolysis and stress-induced malignant hyperthermia events, association with malignant hyperthermia susceptibility, and RYR1 gene sequence variations.

Carsana A.

ScientificWorldJournal. 2013;2013:531465. doi: 10.1155/2013/531465. Epub 2013 Feb 10. Review.

PubMed [citation]

PMID:: 23476141
PMCID:: PMC3582168

Identification of Medically Actionable Secondary Findings in the 1000 Genomes.

Olfson E, Cottrell CE, Davidson NO, Gurnett CA, Heusel JW, Stitziel NO, Chen LS, Hartz S, Nagarajan R, Saccone NL, Bierut LJ.

PLoS One. 2015;10(9):e0135193. doi: 10.1371/journal.pone.0135193.

PubMed [citation]

PMID:: 26332594
PMCID:: PMC4558085

See all PubMed Citations (6)

Details of each submission

From Illumina Laboratory Services, Illumina, SCV001283308.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

#	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, SCV001816185.2

#	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 Glycine with Serine at codon 2160 of the RYR1 protein, p.(Gly2160Ser). The maximum allele frequency for this variant among the six major gnomAD populations is AFR: 0.0006, a frequency consistent with pathogenicity for MHS. This variant has been reported in an individual with a personal or family history of an MH episode and 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_Supporting (PMID:30236257). However, the high MAF in the AFR population in gnomAD precludes the use of PS4. No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). A REVEL score of 0.635 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PM1.

#	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 All of Us Research Program, National Institutes of Health, SCV004820882.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	7	not provided	not provided	clinical testing	PubMed (2)

Description

This missense variant replaces glycine with serine at codon 2160 of the RYR1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least one family affected with malignant hyperthermia susceptibility (PMID: 30236257). This variant has been identified in 24/281882 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		7	not provided	not provided	not provided

Last Updated: Sep 16, 2024

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