VCV000290117.28 - ClinVar

NM_000540.3(RYR1):c.4038C>A (p.Asn1346Lys)

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.

(10)

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.

Conflicting classifications of pathogenicity
Uncertain significance(9); Likely benign(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000540.3(RYR1):c.4038C>A (p.Asn1346Lys)

Variation ID: 290117 Accession: VCV000290117.28

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 19q13.2 19: 38473649 (GRCh38) [ NCBI UCSC ] 19: 38964289 (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	Apr 20, 2024	Feb 5, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000540.3:c.4038C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000531.2:p.Asn1346Lys	missense
NM_001042723.2:c.4038C>A	NP_001036188.1:p.Asn1346Lys	missense
NC_000019.10:g.38473649C>A
NC_000019.9:g.38964289C>A
NG_008866.1:g.44950C>A
LRG_766:g.44950C>A
LRG_766t1:c.4038C>A	LRG_766p1:p.Asn1346Lys

... more HGVS ... less HGVS

Protein change

N1346K

Other names

Canonical SPDI

NC_000019.10:38473648:C:A

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.

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

The Genome Aggregation Database (gnomAD) 0.00006

Trans-Omics for Precision Medicine (TOPMed) 0.00007

Links

ClinGen: CA065501 dbSNP: rs777049924 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.
Malignant hyperthermia, susceptibility to, 1	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Feb 5, 2024	RCV000273611.7
Neuromuscular disease, congenital, with uniform type 1 fiber	Uncertain significance (1)	criteria provided, single submitter	Jun 14, 2016	RCV000313458.5
Congenital multicore myopathy with external ophthalmoplegia	Uncertain significance (1)	criteria provided, single submitter	Jan 13, 2018	RCV000331017.5
Central core myopathy	Uncertain significance (1)	criteria provided, single submitter	Jun 14, 2016	RCV000370505.5
not provided	Conflicting interpretations of pathogenicity (4)	criteria provided, conflicting classifications	Dec 13, 2023	RCV000657029.21
RYR1-related disorder	Uncertain significance (1)	criteria provided, single submitter	Oct 27, 2022	RCV000655552.7

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.
Uncertain significance (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: SCV000412093.2 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016
Uncertain significance (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: SCV000412092.2 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016
Uncertain significance (Aug 24, 2016)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000344618.4 First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=RYR1 Number of individuals with the variant: 1 Sex: mixed
Uncertain significance (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: SCV000412095.3 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. (less)
Uncertain significance (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: SCV000412094.3 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. (less)
Likely benign (Oct 28, 2020)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000589419.3 First in ClinVar: Aug 19, 2017 Last updated: Jul 09, 2018	Comment: This variant is associated with the following publications: (PMID: 29382405)
Uncertain significance (Oct 27, 2022)	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: SCV000777483.6 First in ClinVar: May 28, 2018 Last updated: Feb 07, 2023	Publications: PubMed (2) PubMed: 28492532‚ 29382405 Comment: This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 1346 of the RYR1 protein (p.Asn1346Lys). … (more) This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 1346 of the RYR1 protein (p.Asn1346Lys). This variant is present in population databases (rs777049924, gnomAD 0.02%). This missense change has been observed in individual(s) with congenital myopathy (PMID: 29382405). ClinVar contains an entry for this variant (Variation ID: 290117). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt RYR1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
Uncertain significance (May 15, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV000852596.1 First in ClinVar: Jul 09, 2018 Last updated: Jul 09, 2018
Uncertain significance (Dec 13, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV003813150.2 First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024
Uncertain Significance (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: SCV004820825.1 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)	Publications: PubMed (1) PubMed: 29382405 Comment: This missense variant replaces asparagine with lysine at codon 1346 of the RYR1 protein. Computational prediction suggests that this variant may not impact protein structure … (more) This missense variant replaces asparagine with lysine at codon 1346 of the RYR1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with congenital myopathy, who carried a different pathogenic variant in the same gene (PMID: 29382405). This variant has not been reported in an individual with malignant hyperthermia susceptibility in the literature. This variant has been identified in 17/185820 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less) Number of individuals with the variant: 36

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

Comment:

This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 1346 of the RYR1 protein (p.Asn1346Lys). This variant is present in population databases (rs777049924, gnomAD 0.02%). This missense change has been observed in individual(s) with congenital myopathy (PMID: 29382405). ClinVar contains an entry for this variant (Variation ID: 290117). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt RYR1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Comment:

This missense variant replaces asparagine with lysine at codon 1346 of the RYR1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with congenital myopathy, who carried a different pathogenic variant in the same gene (PMID: 29382405). This variant has not been reported in an individual with malignant hyperthermia susceptibility in the literature. This variant has been identified in 17/185820 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

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
Next-Generation Sequencing to Diagnose Muscular Dystrophy, Rhabdomyolysis, and HyperCKemia.	Wu L	The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques	2018	PMID: 29382405
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=RYR1	-	-	-	-

Text-mined citations for rs777049924 ...

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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_000540.3(RYR1):c.4038C>A (p.Asn1346Lys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs777049924 ...