rs2229139

Variant names:

• chr19-38444640-A-G
• rs2229139
• NM_000540.3:c.594A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000540.3(RYR1):​c.594A>G​(p.Leu198Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.623 in 1,612,584 control chromosomes in the GnomAD database, including 316,828 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.60 (28245 hom., cov: 29)
  • Exomes 𝑓: 0.63 (288583 hom.)
• Consequence: RYR1 NM_000540.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:18 O:1
• Conservation: PhyloP100: 0.221
• Publications: 28 publications found

Genes affected

RYR1 (HGNC:10483): (ryanodine receptor 1) This gene encodes a ryanodine receptor found in skeletal muscle. The encoded protein functions as a calcium release channel in the sarcoplasmic reticulum but also serves to connect the sarcoplasmic reticulum and transverse tubule. Mutations in this gene are associated with malignant hyperthermia susceptibility, central core disease, and minicore myopathy with external ophthalmoplegia. Alternatively spliced transcripts encoding different isoforms have been described. [provided by RefSeq, Jul 2008]

RYR1 Gene-Disease associations (from GenCC):

• malignant hyperthermia, susceptibility to, 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp, Ambry Genetics
• congenital multicore myopathy with external ophthalmoplegia

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp
• RYR1-related myopathy

  Inheritance: AR, AD Classification: DEFINITIVE Submitted by: ClinGen
• central core myopathy

  Inheritance: AD, AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp
• King-Denborough syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• malignant hyperthermia of anesthesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive centronuclear myopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• benign Samaritan congenital myopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• congenital myopathy with myasthenic-like onset

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• lethal multiple pterygium syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 19-38444640-A-G is Benign according to our data. Variant chr19-38444640-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 93277.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.221 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.665 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000540.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR1	NM_000540.3	MANE Select	c.594A>G	p.Leu198Leu	synonymous	Exon 7 of 106	NP_000531.2
	RYR1	NM_001042723.2		c.594A>G	p.Leu198Leu	synonymous	Exon 7 of 105	NP_001036188.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR1	ENST00000359596.8	TSL:5 MANE Select	c.594A>G	p.Leu198Leu	synonymous	Exon 7 of 106	ENSP00000352608.2
	RYR1	ENST00000355481.8	TSL:1	c.594A>G	p.Leu198Leu	synonymous	Exon 7 of 105	ENSP00000347667.3
	RYR1	ENST00000594335.6	TSL:1	n.594A>G		non_coding_transcript_exon	Exon 7 of 103	ENSP00000470927.2

Frequencies

GnomAD3 genomes AF: 0.605 AC: 91574 AN: 151362 Hom.: 28238 Cov.: 29

Gnomad AFR AF: 0.520

Gnomad AMI AF: 0.748

Gnomad AMR AF: 0.675

Gnomad ASJ AF: 0.614

Gnomad EAS AF: 0.624

Gnomad SAS AF: 0.404

Gnomad FIN AF: 0.653

Gnomad MID AF: 0.658

Gnomad NFE AF: 0.643

Gnomad OTH AF: 0.624

GnomAD2 exomes AF: 0.609 AC: 152434 AN: 250168 AF XY: 0.602

Gnomad AFR exome AF: 0.514

Gnomad AMR exome AF: 0.679

Gnomad ASJ exome AF: 0.617

Gnomad EAS exome AF: 0.628

Gnomad FIN exome AF: 0.647

Gnomad NFE exome AF: 0.645

Gnomad OTH exome AF: 0.641

GnomAD4 exome AF: 0.625 AC: 913320 AN: 1461106 Hom.: 288583 Cov.: 51 AF XY: 0.619 AC XY: 449792 AN XY: 726880

African (AFR) AF: 0.513 AC: 17173 AN: 33458

American (AMR) AF: 0.678 AC: 30272 AN: 44648

Ashkenazi Jewish (ASJ) AF: 0.606 AC: 15839 AN: 26126

East Asian (EAS) AF: 0.654 AC: 25948 AN: 39682

South Asian (SAS) AF: 0.415 AC: 35747 AN: 86172

European-Finnish (FIN) AF: 0.645 AC: 34442 AN: 53384

Middle Eastern (MID) AF: 0.618 AC: 3562 AN: 5764

European-Non Finnish (NFE) AF: 0.641 AC: 712677 AN: 1111506

Other (OTH) AF: 0.624 AC: 37660 AN: 60366

GnomAD4 genome AF: 0.605 AC: 91614 AN: 151478 Hom.: 28245 Cov.: 29 AF XY: 0.600 AC XY: 44400 AN XY: 73964

African (AFR) AF: 0.519 AC: 21428 AN: 41250

American (AMR) AF: 0.675 AC: 10276 AN: 15214

Ashkenazi Jewish (ASJ) AF: 0.614 AC: 2128 AN: 3466

East Asian (EAS) AF: 0.625 AC: 3194 AN: 5112

South Asian (SAS) AF: 0.403 AC: 1932 AN: 4796

European-Finnish (FIN) AF: 0.653 AC: 6805 AN: 10426

Middle Eastern (MID) AF: 0.653 AC: 192 AN: 294

European-Non Finnish (NFE) AF: 0.643 AC: 43680 AN: 67908

Other (OTH) AF: 0.618 AC: 1298 AN: 2102

Alfa AF: 0.619 Hom.: 19997

Bravo AF: 0.609

Asia WGS AF: 0.454 AC: 1580 AN: 3478

EpiCase AF: 0.645

EpiControl AF: 0.652

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:18 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:8

Apr 03, 2018

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jan 25, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Aug 15, 2013

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 06, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jan 13, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Leu198Leu in exon 7 of RYR1: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue and is not located wit hin the splice consensus sequence. It has been identified in 47.6% (2096/4406) o f African American chromosomes from a broad population by the NHLBI Exome Sequen cing Project (http://evs.gs.washington.edu/EVS; dbSNP rs2229139).

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Congenital multicore myopathy with external ophthalmoplegia Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Nov 07, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Malignant hyperthermia, susceptibility to, 1 Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Mar 29, 2019

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Central core myopathy Benign:2

Nov 07, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1 Other:1

RYR1 database

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

RYR1-related disorder Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Neuromuscular disease, congenital, with uniform type 1 fiber Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

King Denborough syndrome Benign:1

Nov 07, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	12
DANN	Benign	0.67
PhyloP100		0.22
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2229139; hg19: chr19-38935280; COSMIC: COSV62103826;