rs2229139

Variant names:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

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

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:18O:1

Conservation

PhyloP100: 0.221

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 93277.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-38444640-A-G is described in Lovd as [Benign].

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR1	NM_000540.3 link	c.594A>G	p.Leu198Leu	synonymous_variant	Exon 7 of 106	ENST00000359596.8	NP_000531.2	P21817-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RYR1	ENST00000359596.8 link	c.594A>G	p.Leu198Leu	synonymous_variant	Exon 7 of 106	5	NM_000540.3	ENSP00000352608.2	P21817-1
RYR1	ENST00000355481.8 link	c.594A>G	p.Leu198Leu	synonymous_variant	Exon 7 of 105	1		ENSP00000347667.3	P21817-2
RYR1	ENST00000599547.6 link	n.594A>G		non_coding_transcript_exon_variant	Exon 7 of 80	2		ENSP00000471601.2	M0R127

Frequencies

GnomAD3 genomes

AF:

0.605

AC:

91574

AN:

151362

Hom.:

28238

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.609

AC:

152434

AN:

250168

Hom.:

47428

AF XY:

0.602

AC XY:

81451

AN XY:

135282

show subpopulations

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 SAS exome

AF:

0.404

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.:

AF XY:

0.619

AC XY:

449792

AN XY:

726880

show subpopulations

Gnomad4 AFR exome

AF:

0.513

Gnomad4 AMR exome

AF:

0.678

Gnomad4 ASJ exome

AF:

0.606

Gnomad4 EAS exome

AF:

0.654

Gnomad4 SAS exome

AF:

0.415

Gnomad4 FIN exome

AF:

0.645

Gnomad4 NFE exome

AF:

0.641

Gnomad4 OTH exome

AF:

0.624

GnomAD4 genome

AF:

0.605

AC:

91614

AN:

151478

Hom.:

28245

Cov.:

AF XY:

0.600

AC XY:

44400

AN XY:

73964

show subpopulations

Gnomad4 AFR

AF:

0.519

Gnomad4 AMR

AF:

0.675

Gnomad4 ASJ

AF:

0.614

Gnomad4 EAS

AF:

0.625

Gnomad4 SAS

AF:

0.403

Gnomad4 FIN

AF:

0.653

Gnomad4 NFE

AF:

0.643

Gnomad4 OTH

AF:

0.618

Alfa

AF:

0.623

Hom.:

15676

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:18Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:8

Jun 06, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 03, 2018

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 15, 2013

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

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. -

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). -

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Clinical Genetics, Academic Medical Center

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

Mar 29, 2019

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

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:1Other:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

RYR1 database

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

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 v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.58

CADD

Benign

DANN

Benign

0.67

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over