NM_000540.3:c.12956G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_000540.3(RYR1):c.12956G>A(p.Arg4319Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000778 in 1,022,488 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R4319P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0028 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00044 ( 2 hom. )

Consequence

RYR1
NM_000540.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:6

Conservation

PhyloP100: 0.802

Publications

2 publications found

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 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

RYR1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.020024508).

BP6

Variant 19-38565290-G-A is Benign according to our data. Variant chr19-38565290-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 199217.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00277 (407/146902) while in subpopulation AFR AF = 0.0091 (373/41008). AF 95% confidence interval is 0.00833. There are 1 homozygotes in GnomAd4. There are 203 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 2 AR,AD gene

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.12956G>A	p.Arg4319Gln	missense	Exon 91 of 106	NP_000531.2
	RYR1	NM_001042723.2		c.12941G>A	p.Arg4314Gln	missense	Exon 90 of 105	NP_001036188.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
RYR1	ENST00000359596.8	TSL:5 MANE Select	c.12956G>A	p.Arg4319Gln	missense	Exon 91 of 106	ENSP00000352608.2
RYR1	ENST00000355481.8	TSL:1	c.12941G>A	p.Arg4314Gln	missense	Exon 90 of 105	ENSP00000347667.3
RYR1	ENST00000594335.6	TSL:1	n.*3666G>A		non_coding_transcript_exon	Exon 88 of 103	ENSP00000470927.2

Frequencies

GnomAD3 genomes

AF:

0.00277

AC:

406

AN:

146796

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00910

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000813

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000195

Gnomad SAS

AF:

0.000830

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000197

Gnomad OTH

AF:

0.00198

GnomAD2 exomes

AF:

0.00

AC:

AN:

AF XY:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000443

AC:

388

AN:

875586

Hom.:

Cov.:

AF XY:

0.000468

AC XY:

191

AN XY:

408126

show subpopulations

African (AFR)

AF:

0.00959

AC:

160

AN:

16692

American (AMR)

AF:

0.000407

AC:

AN:

2456

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

6248

East Asian (EAS)

AF:

0.000171

AC:

AN:

5862

South Asian (SAS)

AF:

0.000960

AC:

AN:

17712

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5170

Middle Eastern (MID)

AF:

0.00220

AC:

AN:

1820

European-Non Finnish (NFE)

AF:

0.000224

AC:

177

AN:

789750

Other (OTH)

AF:

0.000937

AC:

AN:

29876

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

114

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00277

AC:

407

AN:

146902

Hom.:

Cov.:

AF XY:

0.00284

AC XY:

203

AN XY:

71520

show subpopulations

African (AFR)

AF:

0.00910

AC:

373

AN:

41008

American (AMR)

AF:

0.000812

AC:

AN:

14786

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3394

East Asian (EAS)

AF:

0.000195

AC:

AN:

5122

South Asian (SAS)

AF:

0.000831

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8570

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.000197

AC:

AN:

65960

Other (OTH)

AF:

0.00196

AC:

AN:

2046

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

104

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00208

Hom.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Mar 13, 2018

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

RYR1: PP3, BS2

Jul 10, 2014

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not specified

Uncertain:1

May 17, 2017

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

A variant of uncertain significance has been identified in the RYR1 gene. The R4319Q variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R4319Q variant is observed in 11/1322 (0.83%) alleles from individuals of African background in large population cohorts and in 42/69576 (0.06%) alleles from individuals undergoing testing at GeneDx (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This substitution occurs at a position where amino acids with similar properties to Arginine are tolerated across species. However, the R4319Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.

Congenital multicore myopathy with external ophthalmoplegia

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.

Malignant hyperthermia, susceptibility to, 1

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

RYR1-related disorder

Benign:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely 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:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Central core myopathy

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.14

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.41

Eigen

Benign

-0.43

Eigen_PC

Benign

-0.48

FATHMM_MKL

Benign

0.065

LIST_S2

Benign

0.76

M_CAP

Pathogenic

0.99

MetaRNN

Benign

0.020

MetaSVM

Uncertain

0.017

MutationAssessor

Benign

1.4

PhyloP100

0.80

PrimateAI

Pathogenic

0.89

PROVEAN

Benign

-0.82

REVEL

Uncertain

0.32

Sift

Benign

0.10

Polyphen

0.71

Vest4

0.12

MutPred

0.25

Loss of methylation at R4314 (P = 0.1002)

MVP

0.96

MPC

0.66

ClinPred

0.50

GERP RS

2.7

PromoterAI

-0.022

Neutral

(source)

Varity_R

0.12

gMVP

0.27

Mutation Taster

=60/40

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over