NM_000540.3(RYR1):c.9796A>C (p.Met3266Leu) AND Malignant hyperthermia, susceptibility to, 1

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Feb 5, 2024
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV003999521.2

Allele description [Variation Report for NM_000540.3(RYR1):c.9796A>C (p.Met3266Leu)]

NM_000540.3(RYR1):c.9796A>C (p.Met3266Leu)

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.9796A>C (p.Met3266Leu)

HGVS:

NC_000019.10:g.38517469A>C
NG_008866.1:g.88770A>C
NM_000540.3:c.9796A>CMANE SELECT
NM_001042723.2:c.9796A>C
NP_000531.2:p.Met3266Leu
NP_000531.2:p.Met3266Leu
NP_001036188.1:p.Met3266Leu
LRG_766t1:c.9796A>C
LRG_766:g.88770A>C
LRG_766p1:p.Met3266Leu
NC_000019.9:g.39008109A>C
NM_000540.2:c.9796A>C

Protein change:

M3266L

Links:

dbSNP: rs201588259

NCBI 1000 Genomes Browser:

rs201588259

Molecular consequence:

NM_000540.3:c.9796A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001042723.2:c.9796A>C - 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

Recent activity

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solute carrier family 12 member 3 isoform 1 [Homo sapiens]
solute carrier family 12 member 3 isoform 1 [Homo sapiens]
gi|1677502245|ref|NP_000330.3|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004820961	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Feb 5, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 29635721, 36283893, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004820961

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Feb 5, 2024)

germline

clinical testing

PubMed (3)
[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	40	not provided	not provided	108544	not provided	clinical testing

Citations

PubMed

Phenotype and genotype of muscle ryanodine receptor rhabdomyolysis-myalgia syndrome.

Witting N, Laforêt P, Voermans NC, Roux-Buisson N, Bompaire F, Rendu J, Duno M, Feillet F, Kamsteeg EJ, Poulsen NS, Dahlqvist JR, Romero NB, Fauré J, Vissing J, Behin A.

Acta Neurol Scand. 2018 May;137(5):452-461. doi: 10.1111/ane.12885. Epub 2017 Dec 29.

PubMed [citation]

PMID:: 29635721

Risk of malignant hyperthermia in patients carrying a variant in the skeletal muscle ryanodine receptor 1 gene.

Janssens L, De Puydt J, Milazzo M, Symoens S, De Bleecker JL, Herdewyn S.

Neuromuscul Disord. 2022 Dec;32(11-12):864-869. doi: 10.1016/j.nmd.2022.10.003. Epub 2022 Oct 19.

PubMed [citation]

PMID:: 36283893

See all PubMed Citations (3)

Details of each submission

From All of Us Research Program, National Institutes of Health, SCV004820961.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	40	not provided	not provided	clinical testing	PubMed (3)

Description

This missense variant replaces methionine with leucine at codon 3266 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 two individuals affected with neuromuscular conditions, one individual was found to be malignant hyperthermia susceptible and one individual was found to be malignant hyperthermia normal (PMID: 29635721, 36283893). This variant has been identified in 33/281826 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		40	not provided	not provided	not provided

Last Updated: Oct 20, 2024

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