NM_000540.3:c.9796A>C

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

2
10
6

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

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
RYR1NM_000540.3 linkc.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
RYR1ENST00000359596.8 linkc.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:
16
AN:
152026
Hom.:
0
Cov.:
31
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:
28
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.:
0
Cov.:
34
AF XY:
0.000114
AC XY:
83
AN XY:
727238
show subpopulations
African (AFR)
AF:
0.0000299
AC:
1
AN:
33478
American (AMR)
AF:
0.000157
AC:
7
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.0000383
AC:
1
AN:
26136
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39700
South Asian (SAS)
AF:
0.0000116
AC:
1
AN:
86258
European-Finnish (FIN)
AF:
0.0000187
AC:
1
AN:
53404
Middle Eastern (MID)
AF:
0.000693
AC:
4
AN:
5768
European-Non Finnish (NFE)
AF:
0.000131
AC:
146
AN:
1112010
Other (OTH)
AF:
0.000132
AC:
8
AN:
60394
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.484
Heterozygous variant carriers
0
14
27
41
54
68
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
10
20
30
40
50
<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:
15
AN:
152144
Hom.:
0
Cov.:
31
AF XY:
0.000108
AC XY:
8
AN XY:
74372
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41498
American (AMR)
AF:
0.000131
AC:
2
AN:
15296
Ashkenazi Jewish (ASJ)
AF:
0.000288
AC:
1
AN:
3468
East Asian (EAS)
AF:
0.000193
AC:
1
AN:
5168
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4822
European-Finnish (FIN)
AF:
0.0000943
AC:
1
AN:
10608
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.000132
AC:
9
AN:
67972
Other (OTH)
AF:
0.000475
AC:
1
AN:
2106
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.600
Heterozygous variant carriers
0
2
3
5
6
8
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<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.:
0
Bravo
AF:
0.000110
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000259
AC:
1
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.0000824
AC:
10
Asia WGS
AF:
0.000289
AC:
1
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
T
BayesDel_noAF
Uncertain
-0.040
CADD
Benign
20
DANN
Benign
0.41
DEOGEN2
Uncertain
0.48
.;T
Eigen
Uncertain
0.27
Eigen_PC
Benign
0.22
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.92
D;D
M_CAP
Uncertain
0.24
D
MetaRNN
Uncertain
0.60
D;D
MetaSVM
Uncertain
0.40
D
MutationAssessor
Uncertain
2.6
M;M
PhyloP100
9.3
PrimateAI
Pathogenic
0.81
D
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
T
GERP RS
4.0
Varity_R
0.47
gMVP
0.56
Mutation Taster
=1/99
disease causing

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

Other links and lift over

dbSNP: rs201588259; hg19: chr19-39008109; API