VCV000133149.41 - ClinVar

NM_000540.3(RYR1):c.5360C>T (p.Pro1787Leu)

Germline

Top reviewed classifications are shown here.

Submission summary:

22 submissions

19 submitters

8 conditions

Reviewed by expert panel

Benign

Mar 2021 by ClinGen Malign… FDA Recognized Database

for Malignant hyperthermia, susceptibility to, 1

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000540.3(RYR1):c.5360C>T (p.Pro1787Leu)

Variation ID: 133149 Accession: VCV000133149.41

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 19q13.2 19: 38486015 (GRCh38) [ NCBI UCSC ] 19: 38976655 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Jun 9, 2014	Oct 20, 2024	Mar 17, 2021

HGVS

Nucleotide	Protein	Molecular consequence
NM_000540.3:c.5360C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000531.2:p.Pro1787Leu	missense
NM_001042723.2:c.5360C>T	NP_001036188.1:p.Pro1787Leu	missense
NC_000019.10:g.38486015C>T
NC_000019.9:g.38976655C>T
NG_008866.1:g.57316C>T
LRG_766:g.57316C>T
LRG_766t1:c.5360C>T	LRG_766p1:p.Pro1787Leu
	P21817:p.Pro1787Leu

... more HGVS ... less HGVS

Protein change

P1787L

Other names

NM_000540.2(RYR1):c.5360C>T

Canonical SPDI

NC_000019.10:38486014:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

0.01697 (T)

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD) 0.01583

Trans-Omics for Precision Medicine (TOPMed) 0.01642

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.01669

1000 Genomes Project 0.01697

1000 Genomes Project 30x 0.01749

The Genome Aggregation Database (gnomAD), exomes 0.01953

Exome Aggregation Consortium (ExAC) 0.01957

Links

ClinGen: CA024515 UniProtKB: P21817#VAR_005599 dbSNP: rs34934920 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
RYR1		No evidence available	No evidence available	GRCh38 GRCh37	8927	9242

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
not provided	Benign (6)	criteria provided, multiple submitters, no conflicts	Apr 1, 2024	RCV000119638.22
not specified	Benign (6)	criteria provided, multiple submitters, no conflicts	Oct 28, 2020	RCV000147431.17
Malignant hyperthermia, susceptibility to, 1	Benign (5)	reviewed by expert panel	Mar 17, 2021	RCV000210010.11
Malignant hypothermia	Benign (1)	criteria provided, single submitter	Mar 25, 2015	RCV000203058.2
Congenital multicore myopathy with external ophthalmoplegia	Benign (1)	criteria provided, single submitter	Jan 13, 2018	RCV000282227.6
Central core myopathy	Benign (1)	criteria provided, single submitter	Jan 13, 2018	RCV000387436.6
Neuromuscular disease, congenital, with uniform type 1 fiber	Likely benign (1)	criteria provided, single submitter	Jun 14, 2016	RCV000374303.6
RYR1-related disorder	Benign (1)	criteria provided, single submitter	Feb 1, 2024	RCV000538850.8

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Benign (Mar 17, 2021)	reviewed by expert panel (ClinGen MHS ACMG Specifications V1) Method: curation	Malignant hyperthermia, susceptibility to, 1 (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen FDA Recognized Database Study: ClinGen Accession: SCV001816196.1 First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021	Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/03ac6f63-5c67-4f58-9c5d-f8c57d7fc777 Comment: This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies … (more) This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions. This sequence variant predicts a substitution of Proline with Leucine at codon 1787 of the RYR1 protein, p.(Pro1787Leu). The maximum allele frequency for this variant among the six major gnomAD populations is SAS: 0.0413, which is considered to be too common for a pathogenic variant causing autosomal dominantly inherited MHS, BA1. This variant has been classified as Benign. Criteria implemented: BA1. (less)
Benign (Mar 25, 2015)	criteria provided, single submitter (DGD Variant Analysis Guidelines) Method: clinical testing	Malignant hypothermia Affected status: unknown Allele origin: unknown	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia Accession: SCV000257713.2 First in ClinVar: Dec 27, 2015 Last updated: Dec 27, 2015
Benign (Mar 21, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV000304960.2 First in ClinVar: Oct 02, 2016 Last updated: Mar 08, 2017
Benign (Oct 28, 2020)	criteria provided, single submitter (Athena Diagnostics criteria) Method: clinical testing	not specified Affected status: unknown Allele origin: unknown	Athena Diagnostics Accession: SCV001880062.1 First in ClinVar: Sep 19, 2021 Last updated: Sep 19, 2021	Publications: PubMed (7) PubMed: 16917943‚ 19191333‚ 23628358‚ 21455645‚ 23183335‚ 21503806‚ 21674524
Benign (Feb 01, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	RYR1-related disorder Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000659963.6 First in ClinVar: Dec 26, 2017 Last updated: Feb 14, 2024
Benign (Nov 22, 2023)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV004563003.1 First in ClinVar: Feb 20, 2024 Last updated: Feb 20, 2024
Benign (Feb 08, 2013)	criteria provided, single submitter (ACMG Guidelines, 2007) Method: clinical testing	not specified (Autosomal unknown) Affected status: unknown Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV000194840.1 First in ClinVar: Nov 23, 2014 Last updated: Nov 23, 2014
Benign (Jul 01, 2013)	criteria provided, single submitter (Gonsalves et al. 2013) Method: research	Malignant hyperthermia, susceptibility to, 1 Affected status: unknown Allele origin: unknown	Biesecker Lab/Clinical Genomics Section, National Institutes of Health Study: ClinSeq Accession: SCV000265710.1 First in ClinVar: Mar 12, 2016 Last updated: Mar 12, 2016 Comment: The study set was not selected for affection status in relation to any myopathy. Pathogenicity categories were based on literature curation. See Pubmed ID: 24195946 … (more) The study set was not selected for affection status in relation to any myopathy. Pathogenicity categories were based on literature curation. See Pubmed ID: 24195946 for details. (less)	Number of individuals with the variant: 43
Likely benign (Jun 14, 2016)	criteria provided, single submitter (ICSL Variant Classification 20161018) Method: clinical testing	Congenital Neuromuscular Disease with Uniform Type 1 Fiber Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000412245.2 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016
Benign (Mar 04, 2016)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	not specified Affected status: yes Allele origin: germline	GeneDx Accession: SCV000522743.4 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Comment: This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at … (more) This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. (less)
Benign (Jan 13, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Malignant hyperthermia, susceptibility to, 1 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000412247.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. (less)
Benign (Jan 13, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Central core myopathy Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000412248.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. (less)
Benign (Jan 13, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Congenital multicore myopathy with external ophthalmoplegia Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000412246.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. (less)
Benign (Mar 05, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Malignant hyperthermia, susceptibility to, 1 Affected status: unknown Allele origin: germline	Color Diagnostics, LLC DBA Color Health Accession: SCV004358087.1 First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024
Benign (Feb 05, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Malignant hyperthermia, susceptibility to, 1 (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	All of Us Research Program, National Institutes of Health Accession: SCV004820858.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 Comment: This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more) This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)	Number of individuals with the variant: 4487
Benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: not provided	not provided (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Breakthrough Genomics, Breakthrough Genomics Accession: SCV005308618.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024
Benign (Apr 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV002822558.14 First in ClinVar: Jan 21, 2023 Last updated: Oct 20, 2024	Comment: RYR1: BS1, BS2 Number of individuals with the variant: 75
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics, Academic Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001924762.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) Study: VKGL Data-share Consensus Accession: SCV001799383.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, University Medical Center Utrecht Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001926386.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001958304.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
not provided (-)	no classification provided Method: not provided	not provided Affected status: not provided Allele origin: unknown	Leiden Muscular Dystrophy (RYR1) Accession: SCV000154545.1 First in ClinVar: Jun 09, 2014 Last updated: Jun 09, 2014
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Comment:

This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions. This sequence variant predicts a substitution of Proline with Leucine at codon 1787 of the RYR1 protein, p.(Pro1787Leu). The maximum allele frequency for this variant among the six major gnomAD populations is SAS: 0.0413, which is considered to be too common for a pathogenic variant causing autosomal dominantly inherited MHS, BA1. This variant has been classified as Benign. Criteria implemented: BA1.

Comment:

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Comment:

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Mutations in RYR1 are a common cause of exertional myalgia and rhabdomyolysis.	Dlamini N	Neuromuscular disorders : NMD	2013	PMID: 23628358
Novel excitation-contraction uncoupled RYR1 mutations in patients with central core disease.	Kraeva N	Neuromuscular disorders : NMD	2013	PMID: 23183335
Dominant and recessive RYR1 mutations in adults with core lesions and mild muscle symptoms.	Duarte ST	Muscle & nerve	2011	PMID: 21674524
Search for genetic variants in the ryanodine receptor 1 gene in patients with symptomatic cerebral vasospasm after aneurysmal subarachnoid hemorrhage.	Rueffert H	Neurocritical care	2011	PMID: 21503806
Ryanodine receptor type 1 gene mutations found in the Canadian malignant hyperthermia population.	Kraeva N	Canadian journal of anaesthesia = Journal canadien d'anesthesie	2011	PMID: 21455645
Functional characterization of ryanodine receptor (RYR1) sequence variants using a metabolic assay in immortalized B-lymphocytes.	Zullo A	Human mutation	2009	PMID: 19191333
Mutations in RYR1 in malignant hyperthermia and central core disease.	Robinson R	Human mutation	2006	PMID: 16917943
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/03ac6f63-5c67-4f58-9c5d-f8c57d7fc777	-	-	-	-

Text-mined citations for rs34934920 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Oct 20, 2024

ClinVar Genomic variation as it relates to human health

NM_000540.3(RYR1):c.5360C>T (p.Pro1787Leu)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs34934920 ...