NM_000540.3(RYR1):c.7300G>A (p.Gly2434Arg) AND not provided

Germline classification:: Pathogenic (11 submissions)
Last evaluated:: Mar 1, 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:: RCV000119698.43

Allele description [Variation Report for NM_000540.3(RYR1):c.7300G>A (p.Gly2434Arg)]

NM_000540.3(RYR1):c.7300G>A (p.Gly2434Arg)

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.7300G>A (p.Gly2434Arg)

Other names:

NM_000540.3(RYR1):c.7300G>A

HGVS:

NC_000019.10:g.38499993G>A
NG_008866.1:g.71294G>A
NM_000540.3:c.7300G>AMANE SELECT
NM_001042723.2:c.7300G>A
NP_000531.2:p.Gly2434Arg
NP_000531.2:p.Gly2434Arg
NP_001036188.1:p.Gly2434Arg
LRG_766t1:c.7300G>A
LRG_766:g.71294G>A
LRG_766p1:p.Gly2434Arg
NC_000019.9:g.38990633G>A
NM_000540.2:c.7300G>A
P21817:p.Gly2434Arg
p.(Gly2434Arg)

Protein change:

G2434R; GLY2434ARG

Links:

PharmGKB: 1183705812PA164749136; PharmGKB: 1183705812PA449461; PharmGKB: 1183705812PA449845; PharmGKB: 1183705812PA450106; PharmGKB: 1183705812PA450434; PharmGKB: 1183705812PA451341; PharmGKB: 1183705812PA451522; UniProtKB: P21817#VAR_005605; OMIM: 180901.0007; dbSNP: rs121918593

NCBI 1000 Genomes Browser:

rs121918593

Molecular consequence:

NM_000540.3:c.7300G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001042723.2:c.7300G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

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
SCV000154605	Leiden Muscular Dystrophy (RYR1)	no classification provided	not provided	unknown	not provided	PubMed (1) [See all records that cite this PMID]
SCV000490785	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Pathogenic (Nov 23, 2016)	germline	clinical testing	Citation Link,
SCV000809466	Gharavi Laboratory, Columbia University	no assertion criteria provided (ACMG Guidelines, 2015)	Pathogenic (Sep 16, 2018)	germline	research	PubMed (1) [See all records that cite this PMID]
SCV000852763	PreventionGenetics, part of Exact Sciences	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 8, 2018)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000925213	Stanford Center for Inherited Cardiovascular Disease, Stanford University	no assertion criteria provided	Pathogenic (Sep 2, 2016)	germline	provider interpretation
SCV001249988	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Pathogenic (Mar 1, 2023)	germline	clinical testing	Citation Link,
SCV001447354	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 23, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001468077	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 25, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001880064	Athena Diagnostics	criteria provided, single submitter (Athena Diagnostics criteria)	Pathogenic (Sep 24, 2020)	unknown	clinical testing	PubMed (20) [See all records that cite these PMIDs] 20681998, 27586648, 9030597, 7849712, 23842196, 19648156, 9334205, 10700782, 30236258, 23628358, 30788618, 28687594, 27646467, 23558838, 18564801, 12151923, 10051009, 9873004, 7881417, 26467025
SCV002019949	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 10, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002501735	AiLife Diagnostics, AiLife Diagnostics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 3, 2022)	germline	clinical testing	PubMed (19) [See all records that cite these PMIDs] 7849712, 31589614, 19648156, 28687594, 11668625, 31206373, 30236258, 30236257, 27586648, 27831900, 31321302, 23842196, 12124989, 27431030, 9334205, 9873004, 29635721, 31447099, 25741868

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	yes	10	not provided	not provided	1	not provided	clinical testing, research
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, provider interpretation
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Novel missense mutations and unexpected multiple changes of RYR1 gene in 75 malignant hyperthermia families.

Tammaro A, Di Martino A, Bracco A, Cozzolino S, Savoia G, Andria B, Cannavo A, Spagnuolo M, Piluso G, Aurino S, Nigro V.

Clin Genet. 2011 May;79(5):438-47. doi: 10.1111/j.1399-0004.2010.01493.x.

PubMed [citation]

PMID:: 20681998

Functional characterization of a distinct ryanodine receptor mutation in human malignant hyperthermia-susceptible muscle.

Richter M, Schleithoff L, Deufel T, Lehmann-Horn F, Herrmann-Frank A.

J Biol Chem. 1997 Feb 21;272(8):5256-60.

PubMed [citation]

PMID:: 9030597

See all PubMed Citations (31)

Details of each submission

From Leiden Muscular Dystrophy (RYR1), SCV000154605.1

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

#	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, SCV000490785.1

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

Description

The G2434R variant in the RYR1 gene has been published previously as a pathogenic variant associated with malignant hyperthermia (Keating et al., 1994; Carpenter et al., 2009; Riazi et al., 2014). The G2434R variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The G2434R variant is a non-conservative amino acid substitution, which occurs at a position that is conserved across species. Based on the ACMG recommendations, G2434R is interpreted as a pathogenic variant.

#	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 Gharavi Laboratory, Columbia University, SCV000809466.1

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

#	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, SCV000852763.1

#	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 Stanford Center for Inherited Cardiovascular Disease, Stanford University, SCV000925213.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	provider interpretation	not provided

#	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 CeGaT Center for Human Genetics Tuebingen, SCV001249988.26

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	9	not provided	not provided	clinical testing	not provided

Description

RYR1: PP1:Strong, PS3, PS4, PM1, PP3, BS2

#	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		9	not provided	not provided	not provided

From Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen, SCV001447354.1

#	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	yes	1	not provided	not provided		not provided	not provided	not provided	not provided

From Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center, SCV001468077.1

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

Description

PS3, PS4, PP1, PP3, PM1

#	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 Athena Diagnostics, SCV001880064.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (20)

Description

The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant is also referred to as p.Gly2433Arg and p.Gly2435Arg in some published literature. Computational tools yielded predictions that this variant may result in the gain of a cryptic splice site without affecting the natural splice sites. This variant segregates with disease in multiple families with susceptibility to malignant hyperthermia. Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant leads to impaired calcium homeostasis (PMID: 9334205, 30236258, 27586648). Computational tools predict that this variant is damaging.

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

From Revvity Omics, Revvity, SCV002019949.3

#	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 AiLife Diagnostics, AiLife Diagnostics, SCV002501735.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (19)

#	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		1	not provided	not provided	not provided

Last Updated: Nov 3, 2024

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