VCV000256470.49 - ClinVar

NM_000540.3(RYR1):c.216G>T (p.Leu72=)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(13)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Benign/Likely benign

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000540.3(RYR1):c.216G>T (p.Leu72=)

Variation ID: 256470 Accession: VCV000256470.49

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 19q13.2 19: 38442399 (GRCh38) [ NCBI UCSC ] 19: 38933039 (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	Dec 6, 2016	Oct 20, 2024	Feb 5, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000540.3:c.216G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000531.2:p.Leu72=	synonymous
NM_001042723.2:c.216G>T	NP_001036188.1:p.Leu72=	synonymous
NC_000019.10:g.38442399G>T
NC_000019.9:g.38933039G>T
NG_008866.1:g.13700G>T
LRG_766:g.13700G>T
LRG_766t1:c.216G>T	LRG_766p1:p.Leu72=

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000019.10:38442398:G: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.

0.00379 (T)

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

The Genome Aggregation Database (gnomAD), exomes 0.00065

Exome Aggregation Consortium (ExAC) 0.00073

The Genome Aggregation Database (gnomAD) 0.00227

Trans-Omics for Precision Medicine (TOPMed) 0.00249

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00254

1000 Genomes Project 30x 0.00344

1000 Genomes Project 0.00379

Links

ClinGen: CA062970 dbSNP: rs113389877 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 specified	Benign/Likely benign (3)	criteria provided, multiple submitters, no conflicts	Jul 25, 2017	RCV000244241.19
Central core myopathy	Likely benign (1)	criteria provided, single submitter	Jun 14, 2016	RCV000338797.7
Malignant hyperthermia, susceptibility to, 1	Benign/Likely benign (3)	criteria provided, multiple submitters, no conflicts	Feb 5, 2024	RCV000279098.10
Congenital multicore myopathy with external ophthalmoplegia	Likely benign (1)	criteria provided, single submitter	Jan 12, 2018	RCV000303429.7
not provided	Benign/Likely benign (3)	criteria provided, multiple submitters, no conflicts	Sep 1, 2022	RCV000540913.30
Neuromuscular disease, congenital, with uniform type 1 fiber	Likely benign (1)	criteria provided, single submitter	Jun 14, 2016	RCV000391152.7
RYR1-related disorder	Benign (1)	criteria provided, single submitter	Jan 29, 2024	RCV001083989.10

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.
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: SCV000411816.2 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016
Likely benign (Jun 14, 2016)	criteria provided, single submitter (ICSL Variant Classification 20161018) Method: clinical testing	Central Core Disease Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000411815.2 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016
Likely benign (Aug 24, 2015)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not specified Affected status: no Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV000596884.1 First in ClinVar: Aug 27, 2017 Last updated: Aug 27, 2017
Benign (Dec 27, 2018)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Athena Diagnostics Accession: SCV001145292.1 First in ClinVar: Jan 18, 2020 Last updated: Jan 18, 2020
Likely benign (Jan 12, 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: SCV000411817.3 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. (less)
Likely benign (Jan 12, 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: SCV000411814.3 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. (less)
Benign (Jul 25, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV000304878.2 First in ClinVar: Oct 03, 2016 Last updated: May 03, 2018
Benign (Sep 22, 2016)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000345758.4 First in ClinVar: Dec 06, 2016 Last updated: May 03, 2018	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=RYR1 http://www.ncbi.nlm.nih.gov/vari… http://www.ncbi.nlm.nih.gov/variation/tools/1000genomes/?chr=19&from=38933039&to=38933039 Number of individuals with the variant: 1 Sex: mixed
Likely benign (Feb 19, 2021)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000531259.5 First in ClinVar: Mar 08, 2017 Last updated: Sep 25, 2021
Benign (Oct 20, 2022)	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: SCV004357260.1 First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024
Benign (Jan 29, 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: SCV000659883.8 First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 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: SCV004823519.1 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: 157
Likely benign (Sep 01, 2022)	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: SCV001500176.23 First in ClinVar: Mar 14, 2021 Last updated: Oct 20, 2024	Comment: RYR1: BP4, BP7 Number of individuals with the variant: 2
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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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely 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
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=RYR1	-	-	-	-
http://www.ncbi.nlm.nih.gov/variation/tools/1000genomes/?chr=19&from=38933039&to=38933039	-	-	-	-

Text-mined citations for rs113389877 ...

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.216G>T (p.Leu72=)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs113389877 ...