NM_000540.3(RYR1):c.7076G>A (p.Arg2359Gln) AND RYR1-related disorder

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Sep 8, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000694878.10

Allele description [Variation Report for NM_000540.3(RYR1):c.7076G>A (p.Arg2359Gln)]

NM_000540.3(RYR1):c.7076G>A (p.Arg2359Gln)

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.7076G>A (p.Arg2359Gln)

Other names:

NM_000540.2(RYR1):c.7076G>A; p.Arg2359Gln

HGVS:

NC_000019.10:g.38499683G>A
NG_008866.1:g.70984G>A
NM_000540.3:c.7076G>AMANE SELECT
NM_001042723.2:c.7076G>A
NP_000531.2:p.Arg2359Gln
NP_000531.2:p.Arg2359Gln
NP_001036188.1:p.Arg2359Gln
LRG_766t1:c.7076G>A
LRG_766:g.70984G>A
LRG_766p1:p.Arg2359Gln
NC_000019.9:g.38990323G>A
NM_000540.2:c.7076G>A

Protein change:

R2359Q

Links:

dbSNP: rs1387126664

NCBI 1000 Genomes Browser:

rs1387126664

Molecular consequence:

NM_000540.3:c.7076G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001042723.2:c.7076G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: RYR1-related disorder
Synonyms:: RYR1-Related Disorders; RYR1-related condition
Identifiers:: MedGen: CN239331

Recent activity

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zinc finger protein with KRAB and SCAN domains 5 isoform a [Homo sapiens]
zinc finger protein with KRAB and SCAN domains 5 isoform a [Homo sapiens]
gi|11036642|ref|NP_055384.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000823342	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Sep 8, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 24433488, 30236257, 28492532
SCV004119722	PreventionGenetics, part of Exact Sciences	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Nov 10, 2022)	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

SCV000823342

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Sep 8, 2023)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV004119722

PreventionGenetics, part of Exact Sciences

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Nov 10, 2022)

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	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Functional and genetic characterization of clinical malignant hyperthermia crises: a multi-centre study.

Klingler W, Heiderich S, Girard T, Gravino E, Heffron JJ, Johannsen S, Jurkat-Rott K, Rüffert H, Schuster F, Snoeck M, Sorrentino V, Tegazzin V, Lehmann-Horn F.

Orphanet J Rare Dis. 2014 Jan 16;9:8. doi: 10.1186/1750-1172-9-8.

PubMed [citation]

PMID:: 24433488
PMCID:: PMC3896768

Genetic epidemiology of malignant hyperthermia in the UK.

Miller DM, Daly C, Aboelsaod EM, Gardner L, Hobson SJ, Riasat K, Shepherd S, Robinson RL, Bilmen JG, Gupta PK, Shaw MA, Hopkins PM.

Br J Anaesth. 2018 Oct;121(4):944-952. doi: 10.1016/j.bja.2018.06.028. Epub 2018 Aug 17.

PubMed [citation]

PMID:: 30236257
PMCID:: PMC6208294

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000823342.6

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

Description

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt RYR1 protein function. ClinVar contains an entry for this variant (Variation ID: 573252). This missense change has been observed in individual(s) with autosomal dominant RYR1-related condition (PMID: 24433488, 30236257; Invitae). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 2359 of the RYR1 protein (p.Arg2359Gln).

#	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 PreventionGenetics, part of Exact Sciences, SCV004119722.1

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

Description

The RYR1 c.7076G>A variant is predicted to result in the amino acid substitution p.Arg2359Gln. This variant has been reported in two unrelated individuals that had malignant hyperthermia episodes and also positive in vitro contracture tests (Klingler et al. 2014. PubMed ID: 24433488; Table S1 - Miller et al. 2018. PubMed ID: 30236257). A different amino acid substitution (p.Arg2359Trp) has also been observed in an individual with malignant hyperthermia (Dekomien et al. 2005. PubMed ID: 16521286). An expert ClinGen curation panel has interpreted this variant as likely pathogenic in relation to autosomal dominant malignant hyperthermia (www.ncbi.nlm.nih.gov/clinvar/variation/573252). This variant is reported in 0.010% of alleles in individuals of Ashkenazi Jewish descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-38990323-G-A). We interpret this variant as likely pathogenic for malignant hyperthermia. To our knowledge, this variant has not been reported in patients with RYR1-related myopathies and it is uncertain if this variant could contribute to a myopathy phenotype. Some malignant hyperthermia variants in the presence of a second RYR1 variant have been reported in cases of autosomal recessive RYR1-related myopathy. THIS PATIENT IS SUSCEPTIBLE TO MALIGNANT HYPERTHERMIA! Alternative anesthetics should be used. The patient should consider wearing an ID bracelet or other alert device (see www.mhaus.org).

#	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

Last Updated: Nov 10, 2024

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