NM_000540.3(RYR1):c.14210G>A (p.Arg4737Gln) AND not provided

Germline classification:: Pathogenic (5 submissions)
Last evaluated:: Dec 2, 2022
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:: RCV000119503.23

Allele description [Variation Report for NM_000540.3(RYR1):c.14210G>A (p.Arg4737Gln)]

NM_000540.3(RYR1):c.14210G>A (p.Arg4737Gln)

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.14210G>A (p.Arg4737Gln)

Other names:

NM_000540.2(RYR1):c.14210G>A

HGVS:

NC_000019.10:g.38577955G>A
NG_008866.1:g.149256G>A
NM_000540.3:c.14210G>AMANE SELECT
NM_001042723.2:c.14195G>A
NP_000531.2:p.Arg4737Gln
NP_000531.2:p.Arg4737Gln
NP_001036188.1:p.Arg4732Gln
LRG_766t1:c.14210G>A
LRG_766:g.149256G>A
LRG_766p1:p.Arg4737Gln
NC_000019.9:g.39068595G>A
NM_000540.2:c.14210G>A
P21817:p.Arg4737Gln
p.(Arg4737Gln)

Protein change:

R4732Q

Links:

UniProtKB: P21817#VAR_045749; dbSNP: rs193922868

NCBI 1000 Genomes Browser:

rs193922868

Molecular consequence:

NM_000540.3:c.14210G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001042723.2:c.14195G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000154410	Leiden Muscular Dystrophy (RYR1)	no classification provided	not provided	unknown	not provided	PubMed (2) [See all records that cite these PMIDs] 16917943, 18564801
SCV000567320	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Dec 2, 2022)	germline	clinical testing	Citation Link,
SCV000852398	PreventionGenetics, part of Exact Sciences	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 19, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002019970	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 25, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002051477	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 16, 2020)	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	unknown	not provided	not provided	not provided	not provided	1	not provided	literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Mutations in RYR1 in malignant hyperthermia and central core disease.

Robinson R, Carpenter D, Shaw MA, Halsall J, Hopkins P.

Hum Mutat. 2006 Oct;27(10):977-89. Review.

PubMed [citation]

PMID:: 16917943

Identification of genetic mutations in Australian malignant hyperthermia families using sequencing of RYR1 hotspots.

Gillies RL, Bjorksten AR, Davis M, Du Sart D.

Anaesth Intensive Care. 2008 May;36(3):391-403.

PubMed [citation]

PMID:: 18564801

See all PubMed Citations (3)

Details of each submission

From Leiden Muscular Dystrophy (RYR1), SCV000154410.1

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	not provided	1	not provided	not provided		not provided	not provided	not provided	not provided

From GeneDx, SCV000567320.4

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

Description

Previously reported, using alternate nomenclature R4893Q, in association with malignant hyperthermia in multiple unrelated individuals (Monnier et al., 2005; Robinson et al., 2006; Gillies et al., 2008; Carpenter et al., 2009); Published functional studies demonstrate a damaging effect (Gomez et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 16917943, 27558158, 25960145, 27663056, 28326467, 16163667, 30788618, 19648156, 30236257, 18564801)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From PreventionGenetics, part of Exact Sciences, SCV000852398.2

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

#	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 Revvity Omics, Revvity, SCV002019970.3

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

#	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 Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center, SCV002051477.3

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

Description

PS3, PP3, PM1, PM2, PM5

#	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: Oct 8, 2024

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