NM_000540.3(RYR1):c.14126C>T (p.Thr4709Met) 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:: RCV001129440.8

Allele description [Variation Report for NM_000540.3(RYR1):c.14126C>T (p.Thr4709Met)]

NM_000540.3(RYR1):c.14126C>T (p.Thr4709Met)

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.14126C>T (p.Thr4709Met)

Other names:

NM_000540.3(RYR1):c.14126C>T

HGVS:

NC_000019.10:g.38573304C>T
NG_008866.1:g.144605C>T
NM_000540.3:c.14126C>TMANE SELECT
NM_001042723.2:c.14111C>T
NP_000531.2:p.Thr4709Met
NP_000531.2:p.Thr4709Met
NP_001036188.1:p.Thr4704Met
LRG_766t1:c.14126C>T
LRG_766:g.144605C>T
LRG_766p1:p.Thr4709Met
NC_000019.9:g.39063944C>T
NM_000540.2:c.14126C>T
NP_000531.2:p.T4709M

Protein change:

T4704M

Links:

dbSNP: rs118192140

NCBI 1000 Genomes Browser:

rs118192140

Molecular consequence:

NM_000540.3:c.14126C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001042723.2:c.14111C>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
SCV001288966	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Uncertain significance (Apr 28, 2017)	germline	clinical testing	Citation Link,
SCV002570145	ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen	reviewed by expert panel (RYR1-MHS Interpretation Guidelines V2)	Uncertain significance (Apr 6, 2023)	germline	curation	Citation Link,
SCV004816257	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Nov 30, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 31107960, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001288966

Illumina Laboratory Services, Illumina

criteria provided, single submitter

(ICSL Variant Classification Criteria 13 December 2019)

Uncertain significance
(Apr 28, 2017)

germline

clinical testing

Citation Link,

SCV002570145

ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen

reviewed by expert panel

(RYR1-MHS Interpretation Guidelines V2)

Uncertain significance
(Apr 6, 2023)

germline

curation

Citation Link,

SCV004816257

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Nov 30, 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	10	not provided	not provided	108544	not provided	clinical testing, curation

Citations

PubMed

Mouse model of severe recessive RYR1-related myopathy.

Brennan S, Garcia-Castañeda M, Michelucci A, Sabha N, Malik S, Groom L, Wei LaPierre L, Dowling JJ, Dirksen RT.

Hum Mol Genet. 2019 Sep 15;28(18):3024-3036. doi: 10.1093/hmg/ddz105.

PubMed [citation]

PMID:: 31107960
PMCID:: PMC6737254

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 Illumina Laboratory Services, Illumina, SCV001288966.1

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

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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled 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, SCV002570145.2

#	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 threonine with methionine at codon 4709 of the RYR1 protein, p.(Thr4709Met). The maximum allele frequency for this variant among the six major gnomAD populations is SAS: 0.00003, a frequency consistent with pathogenicity for MHS. This variant has been reported in individuals with recessive myopathies (PMID:17033962, PMID:21062345, PMID:22473935). A knock-in mouse model does not demonstrate a response to isoflurane in the heterozygous state, this is considered evidence against pathogenicity for autosomal dominantly inherited MH, BS_Supporting (PMID:31107960). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1_Sup (PMID: 21118704). A REVEL score >0.85 (0.901) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PM1_Supporting, PP3_Moderate, BS3_Supporting.

#	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, SCV004816257.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	10	not provided	not provided	clinical testing	PubMed (2)

Description

This missense variant replaces threonine with methionine at codon 4709 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). A functional study using genetically engineered mice showed that mice homozygous for this variant are hypersensitive to isoflurane and experience an increase in core body temperature similar to malignant hyperthermia susceptible mice, but at a slower rate. Further, the study showed that mice heterozygous for this variant were not hypersensitive to isoflurane and did not experience an increase in core temperature compared to wild-type mice (PMID: 31107960). This variant has not been reported in individuals affected with autosomal dominant malignant hyperthermia in the literature, although it is associated with other phenotype(s) (ClinVar variation ID: 65996). This variant has been identified in 12/281074 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Due to insufficient evidence, this variant is classified as a Variant of Uncertain Significance for autosomal dominant malignant hyperthermia.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	108544	not provided	not provided		10	not provided	not provided	not provided

Last Updated: Nov 10, 2024

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