NM_000540.3(RYR1):c.7268T>A (p.Met2423Lys) AND Malignant hyperthermia, susceptibility to, 1

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Dec 13, 2023
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:: RCV003996094.2

Allele description [Variation Report for NM_000540.3(RYR1):c.7268T>A (p.Met2423Lys)]

NM_000540.3(RYR1):c.7268T>A (p.Met2423Lys)

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.7268T>A (p.Met2423Lys)

HGVS:

NC_000019.10:g.38499961T>A
NG_008866.1:g.71262T>A
NM_000540.3:c.7268T>AMANE SELECT
NM_001042723.2:c.7268T>A
NP_000531.2:p.Met2423Lys
NP_000531.2:p.Met2423Lys
NP_001036188.1:p.Met2423Lys
LRG_766t1:c.7268T>A
LRG_766:g.71262T>A
LRG_766p1:p.Met2423Lys
NC_000019.9:g.38990601T>A
NM_000540.2:c.7268T>A
P21817:p.Met2423Lys

Protein change:

M2423K; MET2423LYS

Links:

NCBI 1000 Genomes Browser:

rs118192174

Molecular consequence:

NM_000540.3:c.7268T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001042723.2:c.7268T>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

Recent activity

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FCHSD1 FCH and double SH3 domains 1 [Homo sapiens]
FCHSD1 FCH and double SH3 domains 1 [Homo sapiens]
Gene ID:89848

Gene
89848[uid] AND (alive[prop]) (1)
Gene
Cartilage (Bovine and Shark) (PDQ®) - PDQ Cancer Information Summaries
Cartilage (Bovine and Shark) (PDQ®) - PDQ Cancer Information Summaries
GPD2 [Pantherophis guttatus]
GPD2 [Pantherophis guttatus]
Gene ID:117670303

Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004820909	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 (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004820909

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 (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	germline	unknown	11	not provided	not provided	108544	not provided	clinical testing

Citations

PubMed

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 All of Us Research Program, National Institutes of Health, SCV004820909.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	11	not provided	not provided	clinical testing	PubMed (1)

Description

This missense variant replaces methionine with lysine at codon 2423 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). To our knowledge, functional studies have not been reported for this variant. 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: 12989). This variant has been identified in 5/251410 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		11	not provided	not provided	not provided

Last Updated: Aug 4, 2024

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