VCV000222794.14 - ClinVar

NM_001035.3(RYR2):c.12837G>A (p.Met4279Ile)

Germline

Classification

criteria provided, conflicting classifications. Learn more about how ClinVar calculates review status.

Conflicting classifications of pathogenicity
Uncertain significance(4); Likely benign(1)

5 out of 5 submissions contributed to this 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.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001035.3(RYR2):c.12837G>A (p.Met4279Ile)

Variation ID: 222794 Accession: VCV000222794.14

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1q43 1: 237784549 (GRCh38) [ NCBI UCSC ] 1: 237947849 (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	Mar 1, 2016	Apr 28, 2025	Feb 13, 2025

HGVS

Nucleotide	Protein	Molecular consequence
NM_001035.3:c.12837G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001026.2:p.Met4279Ile	missense
NC_000001.11:g.237784549G>A
NC_000001.10:g.237947849G>A
NG_008799.3:g.747366G>A
LRG_402:g.747366G>A
LRG_402t1:c.12837G>A	LRG_402p1:p.Met4279Ile

... more HGVS ... less HGVS

Protein change

M4279I

Other names

Canonical SPDI

NC_000001.11:237784548:G:A

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), exomes 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00002

Trans-Omics for Precision Medicine (TOPMed) 0.00002

Exome Aggregation Consortium (ExAC) 0.00003

The Genome Aggregation Database (gnomAD) 0.00004

The Genome Aggregation Database (gnomAD) 0.00003

Links

ClinGen: CA085245 dbSNP: rs750117613 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.
RYR2		No evidence available	No evidence available	GRCh38 GRCh37	-	-
LOC126806068	-	-	-	GRCh38	-	452

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.
Primary dilated cardiomyopathy	Uncertain significance (1)	criteria provided, single submitter	Mar 31, 2015	RCV000208489.10
not specified	Uncertain significance (1)	criteria provided, single submitter	Nov 29, 2019	RCV001194102.9
Cardiovascular phenotype	Uncertain significance (1)	criteria provided, single submitter	Feb 13, 2025	RCV002381717.10
Catecholaminergic polymorphic ventricular tachycardia 1	Likely benign (1)	criteria provided, single submitter	Jan 16, 2025	RCV002515553.11
Arrhythmogenic right ventricular dysplasia 2 Catecholaminergic polymorphic ventricular tachycardia 1 Ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome	Uncertain significance (1)	criteria provided, single submitter	Oct 11, 2021	RCV002494544.8

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.	Expand all rows Collapse all rows 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 (Mar 31, 2015) C Contributing to aggregate classification	criteria provided, single submitter (Variant Classification)	Primary dilated cardiomyopathy	Blueprint Genetics Accession: SCV000264191.2 First in ClinVar: Mar 01, 2016 Last updated: Mar 01, 2016 Comment: Found together with likely pathogenic MYH7:NM_000257.2:c.5741_5744delinsT	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes Number of individuals with the variant: 1

Likely benign (Jan 16, 2025) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Catecholaminergic polymorphic ventricular tachycardia 1	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000760681.7 First in ClinVar: May 28, 2018 Last updated: Feb 25, 2025	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Uncertain significance (Nov 29, 2019) C Contributing to aggregate classification	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	not specified	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV001363383.1 First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020	Comment: show Variant summary: RYR2 c.12837G>A (p.Met4279Ile) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 248598 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.12837G>A in individuals affected with Arrhythmia and no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submissions (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Uncertain significance (Feb 13, 2025) C Contributing to aggregate classification	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Cardiovascular phenotype	Ambry Genetics Accession: SCV002691137.3 First in ClinVar: Nov 29, 2022 Last updated: Apr 28, 2025	Comment: show The p.M4279I variant (also known as c.12837G>A), located in coding exon 90 of the RYR2 gene, results from a G to A substitution at nucleotide position 12837. The methionine at codon 4279 is replaced by isoleucine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Uncertain significance (Oct 11, 2021) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome Catecholaminergic polymorphic ventricular tachycardia 1 Catecholaminergic polymorphic ventricular tachycardia 1	Fulgent Genetics, Fulgent Genetics Accession: SCV002796990.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022	Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown

Comment:

Variant summary: RYR2 c.12837G>A (p.Met4279Ile) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 248598 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.12837G>A in individuals affected with Arrhythmia and no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submissions (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

Comment:

The p.M4279I variant (also known as c.12837G>A), located in coding exon 90 of the RYR2 gene, results from a G to A substitution at nucleotide position 12837. The methionine at codon 4279 is replaced by isoleucine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Citations for germline classification of this variant

There are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar.

Text-mined citations for rs750117613 ...

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 May 17, 2025

ClinVar Genomic variation as it relates to human health

NM_001035.3(RYR2):c.12837G>A (p.Met4279Ile)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Citations for germline classification of this variant

Text-mined citations for rs750117613 ...