chr1-237445427-G-A

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1PM2PP2PP3_Strong

The NM_001035.3(RYR2):​c.1197G>A​(p.Met399Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). 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. M399V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

RYR2
NM_001035.3 missense

Scores

15
2
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 10.0

Publications

2 publications found
Variant links:
Genes affected
RYR2 (HGNC:10484): (ryanodine receptor 2) This gene encodes a ryanodine receptor found in cardiac muscle sarcoplasmic reticulum. The encoded protein is one of the components of a calcium channel, composed of a tetramer of the ryanodine receptor proteins and a tetramer of FK506 binding protein 1B proteins, that supplies calcium to cardiac muscle. Mutations in this gene are associated with stress-induced polymorphic ventricular tachycardia and arrhythmogenic right ventricular dysplasia. [provided by RefSeq, Jul 2008]
RYR2 Gene-Disease associations (from GenCC):
  • arrhythmogenic right ventricular dysplasia 2
    Inheritance: AD Classification: DEFINITIVE, NO_KNOWN Submitted by: Laboratory for Molecular Medicine, Ambry Genetics
  • catecholaminergic polymorphic ventricular tachycardia
    Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen, G2P
  • catecholaminergic polymorphic ventricular tachycardia 1
    Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
  • hypertrophic cardiomyopathy
    Inheritance: AD Classification: LIMITED Submitted by: ClinGen
  • arrhythmogenic right ventricular cardiomyopathy
    Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

PM1
In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 17 uncertain in NM_001035.3
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in the RYR2 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 195 curated pathogenic missense variants (we use a threshold of 10). The gene has 55 curated benign missense variants. Gene score misZ: 5.7809 (above the threshold of 3.09). Trascript score misZ: 6.4158 (above the threshold of 3.09). GenCC associations: The gene is linked to hypertrophic cardiomyopathy, catecholaminergic polymorphic ventricular tachycardia 1, catecholaminergic polymorphic ventricular tachycardia, arrhythmogenic right ventricular dysplasia 2, arrhythmogenic right ventricular cardiomyopathy.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.948

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RYR2NM_001035.3 linkc.1197G>A p.Met399Ile missense_variant Exon 14 of 105 ENST00000366574.7 NP_001026.2 Q92736-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RYR2ENST00000366574.7 linkc.1197G>A p.Met399Ile missense_variant Exon 14 of 105 1 NM_001035.3 ENSP00000355533.2 Q92736-1
RYR2ENST00000661330.2 linkc.1197G>A p.Met399Ile missense_variant Exon 14 of 106 ENSP00000499393.2 A0A590UJF6
RYR2ENST00000609119.2 linkn.1197G>A non_coding_transcript_exon_variant Exon 14 of 104 5 ENSP00000499659.2 A0A590UK06

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Aug 23, 2013
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The Met399Ile variant in RYR2 has not been reported in individuals with cardiomy opathy or in large population studies. Computational analyses (biochemical amino acid properties, conservation, PolyPhen2, and SIFT) suggest that this variant m ay impact the protein, though this information is not predictive enough to deter mine pathogenicity. Additional information is needed to fully assess the clinica l significance of the Met399Ile variant. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.95
BayesDel_addAF
Pathogenic
0.30
D
BayesDel_noAF
Pathogenic
0.19
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.92
D;D
Eigen
Pathogenic
0.75
Eigen_PC
Pathogenic
0.70
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.99
D;D
M_CAP
Pathogenic
0.76
D
MetaRNN
Pathogenic
0.95
D;D
MetaSVM
Pathogenic
0.81
D
MutationAssessor
Pathogenic
3.0
M;.
PhyloP100
10
PrimateAI
Pathogenic
0.80
T
PROVEAN
Uncertain
-3.2
D;.
REVEL
Pathogenic
0.70
Sift
Pathogenic
0.0
D;.
Polyphen
0.96
D;.
Vest4
0.77
MutPred
0.80
Loss of disorder (P = 0.0836);.;
MVP
0.95
MPC
0.87
ClinPred
0.98
D
GERP RS
5.8
Varity_R
0.96
gMVP
0.67
Mutation Taster
=9/91
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: rs727503397; hg19: chr1-237608727; COSMIC: COSV104666967; API