NM_000540.3:c.9796A>C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP6

The NM_000540.3(RYR1):c.9796A>C(p.Met3266Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000114 in 1,614,016 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M3266T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000099 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

RYR1
NM_000540.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:2

Conservation

PhyloP100: 9.27

Publications

3 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: Likely_benign. The variant received -1 ACMG points.

BP6

Variant 19-38517469-A-C is Benign according to our data. Variant chr19-38517469-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 478302.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR1	NM_000540.3 link	c.9796A>C	p.Met3266Leu	missense_variant	Exon 66 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.9796A>C	p.Met3266Leu	missense_variant	Exon 66 of 106	5	NM_000540.3	ENSP00000352608.2		P21817-1

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

152026

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.000480

GnomAD2 exomes

AF:

0.000112

AC:

AN:

250522

AF XY:

0.000111

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000202

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000159

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000116

AC:

169

AN:

1461872

Hom.:

Cov.:

AF XY:

0.000114

AC XY:

AN XY:

727238

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33478

American (AMR)

AF:

0.000157

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53404

Middle Eastern (MID)

AF:

0.000693

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000131

AC:

146

AN:

1112010

Other (OTH)

AF:

0.000132

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000986

AC:

AN:

152144

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74372

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41498

American (AMR)

AF:

0.000131

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3468

East Asian (EAS)

AF:

0.000193

AC:

AN:

5168

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.0000943

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000132

AC:

AN:

67972

Other (OTH)

AF:

0.000475

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.600

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:

0.000189

Hom.:

Bravo

AF:

0.000110

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000824

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000491

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Oct 31, 2023

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 30, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 29635721) -

Mar 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

RYR1: PP3, BS2 -

RYR1-related disorder

Uncertain:1

Dec 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces methionine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 3266 of the RYR1 protein (p.Met3266Leu). This variant is present in population databases (rs201588259, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of central core disease and/or myalgia and elevated creatine kinase levels (PMID: 29635721, 36283893). ClinVar contains an entry for this variant (Variation ID: 478302). 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) indicates that this missense variant is not expected to disrupt RYR1 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Malignant hyperthermia, susceptibility to, 1

Uncertain:1

Aug 23, 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 methionine with leucine at codon 3266 of the RYR1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 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 neuromuscular conditions, one individual was found to be malignant hyperthermia susceptible and one individual was found to be malignant hyperthermia normal (PMID: 29635721, 36283893). This variant has been identified in 33/281826 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

RYR1-related myopathy

Uncertain:1

Feb 05, 2024

Molecular Genetics, Royal Melbourne Hospital

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change in RYR1 is predicted to replace methionine with leucine at codon 3266, p.(Met3266Leu). The methionine residue is highly conserved (100 vertebrates, Multiz Alignments), and is located in exon 66 in the cytoplasmic domain. There is a small physicochemical difference between methionine and leucine. The highest population minor allele frequency in the population database gnomAD v4.0 is 0.01% (155/1,179,982 alleles) in the European (non-Finnish) population, which is consistent with recessive disease. This variant has been classified as likely benign or as a variant of uncertain significance (ClinVar ID: 478302). The variant has been detected in at least two individuals with malignant hyperthermia (MH) susceptibility and one individual MH negative by in vitro muscle contracture testing, with variable muscle disease features (PMID: 29635721, 36283893; Royal Melbourne Hospital). Computational evidence is uninformative for the missense substitution (REVEL = 0.55). Based on the classification scheme RMH ACMG Guidelines v1.6.1, this variant is classified as a VARIANT of UNCERTAIN SIGNIFICANCE. Following criteria is met: PM2_Supporting. -

Congenital myasthenic syndrome 12

Uncertain:1

Feb 25, 2022

MGZ Medical Genetics Center

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.45

BayesDel_addAF

Benign

-0.052

BayesDel_noAF

Uncertain

-0.040

CADD

Benign

(source)

DANN

Benign

0.41

DEOGEN2

Uncertain

0.48

.;T

Eigen

Uncertain

0.27

Eigen_PC

Benign

0.22

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.92

D;D

M_CAP

Uncertain

0.24

MetaRNN

Uncertain

0.60

D;D

MetaSVM

Uncertain

0.40

MutationAssessor

Uncertain

2.6

M;M

PhyloP100

9.3

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

-2.0

N;N

REVEL

Uncertain

0.55

Sift

Benign

0.23

T;T

Polyphen

0.65

P;P

Vest4

0.63

MutPred

0.31

Loss of phosphorylation at Y3263 (P = 0.0917);Loss of phosphorylation at Y3263 (P = 0.0917);

MVP

0.93

MPC

0.29

ClinPred

0.38

GERP RS

4.0

Varity_R

0.47

gMVP

0.56

Mutation Taster

=1/99

disease causing

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over