NM_000540.3(RYR1):c.14954A>G (p.Asn4985Ser) AND Malignant hyperthermia, susceptibility to, 1

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Apr 3, 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:: RCV004007810.2

Allele description [Variation Report for NM_000540.3(RYR1):c.14954A>G (p.Asn4985Ser)]

NM_000540.3(RYR1):c.14954A>G (p.Asn4985Ser)

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.14954A>G (p.Asn4985Ser)

HGVS:

NC_000019.10:g.38586176A>G
NG_008866.1:g.157477A>G
NM_000540.3:c.14954A>GMANE SELECT
NM_001042723.2:c.14939A>G
NP_000531.2:p.Asn4985Ser
NP_000531.2:p.Asn4985Ser
NP_001036188.1:p.Asn4980Ser
LRG_766t1:c.14954A>G
LRG_766:g.157477A>G
LRG_766p1:p.Asn4985Ser
NC_000019.9:g.39076816A>G
NM_000540.2:c.14954A>G

Protein change:

N4980S

Molecular consequence:

NM_000540.3:c.14954A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001042723.2:c.14939A>G - 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

Clear Turn Off Turn On

ATP6AP2 [Malurus melanocephalus]
ATP6AP2 [Malurus melanocephalus]
Gene ID:130580617

Gene
ATP6V1A [Mesitornis unicolor]
ATP6V1A [Mesitornis unicolor]
Gene ID:104541713

Gene

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004816288	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Apr 3, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 21118704, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004816288

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Apr 3, 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	1	not provided	not provided	108544	not provided	clinical testing

Citations

PubMed

Mechanistic models for muscle diseases and disorders originating in the sarcoplasmic reticulum.

Maclennan DH, Zvaritch E.

Biochim Biophys Acta. 2011 May;1813(5):948-64. doi: 10.1016/j.bbamcr.2010.11.009. Epub 2010 Nov 27. Review.

PubMed [citation]

PMID:: 21118704

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, SCV004816288.1

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

Description

This missense variant replaces asparagine with serine at codon 4985 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). Although functional studies have not been reported for this variant, it occurs in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to malignant hyperthermia susceptibility (PMID: 21118704). This variant has not been reported in individuals affected with malignant hyperthermia in the literature. This variant has not been identified 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		1	not provided	not provided	not provided

Last Updated: May 7, 2024

ClinVar

Relating variation to medicine