NM_000540.3(RYR1):c.13885G>A (p.Val4629Met) AND Malignant hyperthermia, susceptibility to, 1

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Nov 28, 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:: RCV004008982.2

Allele description [Variation Report for NM_000540.3(RYR1):c.13885G>A (p.Val4629Met)]

NM_000540.3(RYR1):c.13885G>A (p.Val4629Met)

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.13885G>A (p.Val4629Met)

HGVS:

NC_000019.10:g.38572157G>A
NG_008866.1:g.143458G>A
NM_000540.3:c.13885G>AMANE SELECT
NM_001042723.2:c.13870G>A
NP_000531.2:p.Val4629Met
NP_001036188.1:p.Val4624Met
LRG_766t1:c.13885G>A
LRG_766:g.143458G>A
NC_000019.9:g.39062797G>A
NM_000540.2:c.13885G>A

Protein change:

V4624M

Links:

dbSNP: rs752668333

NCBI 1000 Genomes Browser:

rs752668333

Molecular consequence:

NM_000540.3:c.13885G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001042723.2:c.13870G>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
SCV004816250	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Nov 28, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 21911697, 25214167, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004816250

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Nov 28, 2023)

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	5	not provided	not provided	108544	not provided	clinical testing

Citations

PubMed

Muscle magnetic resonance imaging in congenital myopathies due to ryanodine receptor type 1 gene mutations.

Klein A, Jungbluth H, Clement E, Lillis S, Abbs S, Munot P, Pane M, Wraige E, Schara U, Straub V, Mercuri E, Muntoni F.

Arch Neurol. 2011 Sep;68(9):1171-9. doi: 10.1001/archneurol.2011.188.

PubMed [citation]

PMID:: 21911697

MotorPlex provides accurate variant detection across large muscle genes both in single myopathic patients and in pools of DNA samples.

Savarese M, Di Fruscio G, Mutarelli M, Torella A, Magri F, Santorelli FM, Comi GP, Bruno C, Nigro V.

Acta Neuropathol Commun. 2014 Sep 11;2:100. doi: 10.1186/s40478-014-0100-3.

PubMed [citation]

PMID:: 25214167
PMCID:: PMC4172906

See all PubMed Citations (3)

Details of each submission

From All of Us Research Program, National Institutes of Health, SCV004816250.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	5	not provided	not provided	clinical testing	PubMed (3)

Description

This missense variant replaces valine with methionine at codon 4629 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 not been reported in individuals affected with autosomal dominant malignant hyperthermia in the literature, although it has been reported in individuals affected with other phenotypes (PMID: 21911697, 25214167). This variant has been identified in 2/251476 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		5	not provided	not provided	not provided

Last Updated: Jul 29, 2024

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