NM_000540.3(RYR1):c.1598G>A (p.Arg533His) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (6 submissions)
Last evaluated:: Oct 31, 2024
Review status:: criteria provided, conflicting classifications

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:: RCV000119578.50

Allele description [Variation Report for NM_000540.3(RYR1):c.1598G>A (p.Arg533His)]

NM_000540.3(RYR1):c.1598G>A (p.Arg533His)

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.1598G>A (p.Arg533His)

Other names:

NM_000540.3(RYR1):c.1598G>A

HGVS:

NC_000019.10:g.38455472G>A
NG_008866.1:g.26773G>A
NM_000540.3:c.1598G>AMANE SELECT
NM_001042723.2:c.1598G>A
NP_000531.2:p.Arg533His
NP_000531.2:p.Arg533His
NP_001036188.1:p.Arg533His
LRG_766t1:c.1598G>A
LRG_766:g.26773G>A
LRG_766p1:p.Arg533His
NC_000019.9:g.38946112G>A
NM_000540.2:c.1598G>A
NM_000540.3:c.1598G>A
P21817:p.Arg533His
p.(Arg533His)

Protein change:

R533H

Links:

UniProtKB: P21817#VAR_008971; dbSNP: rs144336148

NCBI 1000 Genomes Browser:

rs144336148

Molecular consequence:

NM_000540.3:c.1598G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001042723.2:c.1598G>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
SCV000154485	Leiden Muscular Dystrophy (RYR1)	no classification provided	not provided	unknown	not provided	PubMed (2) [See all records that cite these PMIDs] 16917943, 16732084
SCV000203448	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions 2015)	Uncertain significance (Jun 6, 2016)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 23459219, 24055113 Citation Link,
SCV001151809	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Likely pathogenic (Aug 1, 2024)	germline	clinical testing	Citation Link,
SCV001782464	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Likely pathogenic (Oct 31, 2024)	germline	clinical testing	Citation Link,
SCV002502822	AiLife Diagnostics, AiLife Diagnostics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Dec 16, 2021)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 10484775, 25637381, 24055113, 30236257, 23459219, 25741868
SCV003813052	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Aug 30, 2023)	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	3	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	10	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	not provided	not provided	not provided	not provided	1	not provided	literature only

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

Malignant hyperthermia in Japan: mutation screening of the entire ryanodine receptor type 1 gene coding region by direct sequencing.

Ibarra M CA, Wu S, Murayama K, Minami N, Ichihara Y, Kikuchi H, Noguchi S, Hayashi YK, Ochiai R, Nishino I.

Anesthesiology. 2006 Jun;104(6):1146-54.

PubMed [citation]

PMID:: 16732084

See all PubMed Citations (8)

Details of each submission

From Leiden Muscular Dystrophy (RYR1), SCV000154485.1

#	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 Eurofins Ntd Llc (ga), SCV000203448.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	3	not provided	not provided	clinical testing	PubMed (2)

#	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		3	not provided	not provided	not provided

From CeGaT Center for Human Genetics Tuebingen, SCV001151809.27

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

Description

RYR1: PM1, PM5, PS4:Moderate, PS3:Supporting

#	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 GeneDx, SCV001782464.8

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

Description

Published functional studies demonstrate a damaging effect with increased sensitivity to a RYR1 agonist compared to wild-type controls (PMID: 23459219); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 10484775, 24055113, 25637381, 27147545, 30236257, 11668625, 31301762, 33767344, 32381029, 32919876, Kanzaki2022[Paper], 35718563, 34890165, 16732084, 23459219, 30499100, 16084090, 16917943)

#	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 AiLife Diagnostics, AiLife Diagnostics, SCV002502822.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (6)

#	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

From Revvity Omics, Revvity, SCV003813052.2

#	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

Last Updated: Nov 10, 2024

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