19-38477821-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PP3_ModeratePP5

The NM_000540.3(RYR1):c.4405C>T(p.Arg1469Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000212 in 1,410,288 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R1469Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00022 ( 0 hom. )

Consequence

RYR1
NM_000540.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:13U:5

Conservation

PhyloP100: 2.58

Publications

8 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: Uncertain_significance. The variant received 3 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.928

PP5

Variant 19-38477821-C-T is Pathogenic according to our data. Variant chr19-38477821-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 161372.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR1	NM_000540.3 link	c.4405C>T	p.Arg1469Trp	missense_variant	Exon 30 of 106	ENST00000359596.8	NP_000531.2	P21817-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8 link	c.4405C>T	p.Arg1469Trp	missense_variant	Exon 30 of 106	5	NM_000540.3	ENSP00000352608.2		P21817-1

Frequencies

GnomAD3 genomes

AF:

0.000106

AC:

AN:

142090

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000256

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000214

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000143

AC:

AN:

251126

AF XY:

0.000110

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000282

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000224

AC:

284

AN:

1268088

Hom.:

Cov.:

AF XY:

0.000243

AC XY:

153

AN XY:

628996

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

27848

American (AMR)

AF:

0.0000258

AC:

AN:

38692

Ashkenazi Jewish (ASJ)

AF:

0.000106

AC:

AN:

18836

East Asian (EAS)

AF:

0.0000449

AC:

AN:

22264

South Asian (SAS)

AF:

0.0000237

AC:

AN:

84516

European-Finnish (FIN)

AF:

0.00

AC:

AN:

36246

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4754

European-Non Finnish (NFE)

AF:

0.000276

AC:

273

AN:

987510

Other (OTH)

AF:

0.000105

AC:

AN:

47422

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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:

0.000105

AC:

AN:

142200

Hom.:

Cov.:

AF XY:

0.000116

AC XY:

AN XY:

68924

show subpopulations

African (AFR)

AF:

0.0000256

AC:

AN:

39106

American (AMR)

AF:

0.00

AC:

AN:

14190

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3352

East Asian (EAS)

AF:

0.00

AC:

AN:

4106

South Asian (SAS)

AF:

0.00

AC:

AN:

3972

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8946

Middle Eastern (MID)

AF:

0.00

AC:

AN:

284

European-Non Finnish (NFE)

AF:

0.000214

AC:

AN:

65350

Other (OTH)

AF:

0.00

AC:

AN:

2030

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

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:

0.000166

Hom.:

Bravo

AF:

0.000110

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000140

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000533

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:13Uncertain:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:4Uncertain:2

Jul 29, 2021

Revvity Omics, Revvity

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 16, 2025

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Identified as heterozygous in individuals with possible susceptibility to malignant hyperthermia based on IVCT testing; however, these individuals also carried additional variants in RYR1 and detailed clinical and segregation information was not provided (PMID: 25735680, 25658027); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25637381, 26332594, 31407473, 30652412, 34463354, 27452334, 31680123, 20839240, 37937776, 38127101, 36939041, 25735680, 25658027) -

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

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Aug 28, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PP3, PM3_strong, PS4 -

RYR1-related disorder

Pathogenic:3

Aug 28, 2024

PreventionGenetics, part of Exact Sciences

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The RYR1 c.4405C>T variant is predicted to result in the amino acid substitution p.Arg1469Trp. This variant was reported in two siblings that also had a truncating RYR1 variant and was presumably causative for a recessive RYR1 congenital myopathy (Wilmshurst et al. 2010. PubMed ID: 20839240). In another congenital myopathy patient, the c.4405C>T was found on the opposite allele as a pathogenic splice variant (Klein et al. 2012. PubMed ID: 22473935). This variant has also been reported in patients with malignant hyperthermia susceptibility; however, the evidence for pathogenicity was not established with segregation or functional evidence (Fiszer et al. 2015. PubMed ID: 25658027; Gillies et al. 2015. PubMed ID: 25735680). We have also observed this variant in the compound heterozygous state at PreventionGenetics in two other patients with congenital myopathy. This variant is reported in 0.028% of alleles in individuals of European (Non-Finnish) descent in gnomAD. In summary, this variant is categorized as likely pathogenic for autosomal recessive RYR1-related myopathy. -

Dec 09, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1469 of the RYR1 protein (p.Arg1469Trp). This variant is present in population databases (rs200546266, gnomAD 0.03%). This missense change has been observed in individual(s) with clinical features of autosomal recessive congenital myopathy (PMID: 20839240, 21911697, 30652412, 31407473; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant has been reported in individual(s) with autosomal dominant malignant hyperthermia susceptibility (PMID: 25658027, 25735680); however, the role of the variant in this condition is currently unclear. ClinVar contains an entry for this variant (Variation ID: 161372). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RYR1 protein function. For these reasons, this variant has been classified as Pathogenic. -

Jan 12, 2022

Illumina Laboratory Services, Illumina

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Neuromuscular disease

Pathogenic:1

Mar 09, 2023

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Arg1469Trp variant in RYR1 has been reported in 7 compound heterozygous probands who had either congenital myopathy, arthrogryposis, or minicore myopathy and segregated in at least 1 affected sibling (cis/trans not determined; Wilmshurst 2010 PMID: 20839240, Klein 2011 PMID: 21911697, Klein 2012 PMID: 22473935, Pergande 2020 PMID: 31680123, Alkhunaizi 2019 PMID: 30652412, Maggi 2013 PMID: 23394784, Krenn 2020 PMID: 31407473, Reumers 2021 PMID: 34463354). It has also been previously reported in 2 individuals with malignant hyperthermia (Fiszer 2015 PMID: 25658027, Gillies 2015 PMID: 25735680) and has been identified in ClinVar (Variation ID 161372). It has also been identified in 14/65346 (0.021%) European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that the p.Arg1469Trp variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive congenital myopathy. ACMG/AMP Criteria applied: PM3_VeryStrong, PP4, PP3. -

Congenital multicore myopathy with external ophthalmoplegia

Pathogenic:1

May 21, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: RYR1 c.4405C>T (p.Arg1469Trp) results in a non-conservative amino acid change located in the B30.2/SPRY domain (IPR001870) of the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change. The variant allele was found at a frequency of 0.00014 in 251126 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in RYR1 causing Congenital multicore myopathy with external ophthalmoplegia (0.00014 vs 0.0011), allowing no conclusion about variant significance. c.4405C>T has been reported in the literature in at-least four individuals affected with Autosomal Recessive RYR1-related diseases, inclcuding AR minicore myopathy (Krenn_2020, Krenn_2024, Klein_2011, LCG internal data), AR Fetal Akinesia/decreased fetal movement (Pergrande_2020), features of congenital myopathy-1B (Meng_2023) and AR hypotonia with increased fiber size variation (central core type I fiber predominance) (Dosi_2023). These data indicate that the variant is very likely to be associated with AR RYR1-related diseases. The variant also has been reported in the literature as isolated cases in a variety of AD conditions, including RYR1-related Congenital Myopathy with Central Nuclei (Wilmhurst_2010) or congenital fiber-type disproportion (Pinto_2022), Centronuclear myopathy (CNM) (Reumers_2021), pulmonary hypoplasia and AMC (Pergrande_2020, Alkhunaizi_2019), and susceptibility to Malignant Hyperthermia/Rhabdomyolysis (Gillies_2015, Fiszer_2015, Kruijt_2021). The reported assertions were mostly VUS in settings of central core myopathy and Rhabdomyolysis susceptibility (Reumers_2021, Kruijt_2021, Gillies_2015, Fiszer_2015). Thus the evidence for pathogenicity in AD RYR1-related disease was not established. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 30652412, 36833224, 25658027, 25735680, 21911697, 38127101, 31407473, 32978841, 36939041, 31680123, 35548885, 34463354, 20839240). ClinVar contains an entry for this variant (Variation ID: 161372). Based on the evidence outlined above, the variant was classified as pathogenic. -

Fetal akinesia deformation sequence 1;C5779613:Arthrogryposis multiplex congenita

Pathogenic:1

Jun 28, 2019

Cirak Lab, University Hospital Cologne

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Congenital myopathy with fiber type disproportion

Pathogenic:1

Aug 12, 2019

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PP2,PP3,BS2. -

See cases

Pathogenic:1

Mar 05, 2024

Institute of Human Genetics, University Hospital Muenster

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ACMG categories: PM3,PP2,PP3,PP5_mod -

King Denborough syndrome

Pathogenic:1

Jun 01, 2022

Solve-RD Consortium

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:provider interpretation

Variant confirmed as disease-causing by referring clinical team -

not specified

Uncertain:1

Dec 07, 2016

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Malignant hyperthermia, susceptibility to, 1

Uncertain:1

Jul 10, 2024

All of Us Research Program, National Institutes of Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces arginine with tryptophan at codon 1469 of the RYR1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with autosomal dominant malignant hyperthermia (PMID: 25658027, 25735680) and is associated with other phenotype(s) (ClinVar Variation ID: 161372). This variant has been identified in 36/251126 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Due to insufficient evidence, this variant is classified as a Variant of Uncertain Significance for autosomal dominant malignant hyperthermia. -

Congenital myopathy

Uncertain:1

Jun 01, 2014

CSER _CC_NCGL, University of Washington

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.42

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Pathogenic

0.22

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.85

.;D

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Uncertain

0.87

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Pathogenic

0.46

MetaRNN

Pathogenic

0.93

D;D

MetaSVM

Uncertain

-0.040

MutationAssessor

Uncertain

2.8

M;M

PhyloP100

2.6

PrimateAI

Uncertain

0.61

PROVEAN

Pathogenic

-4.9

D;D

REVEL

Pathogenic

0.77

Sift

Uncertain

0.011

D;D

Polyphen

1.0

D;D

Vest4

0.86

MVP

0.88

MPC

1.0

ClinPred

0.90

GERP RS

3.3

Varity_R

0.26

gMVP

0.91

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over