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
Consequence
NM_001035.3 missense
Scores
Clinical Significance
Conservation
Publications
- arrhythmogenic right ventricular dysplasia 2Inheritance: AD Classification: DEFINITIVE, NO_KNOWN Submitted by: Laboratory for Molecular Medicine, Ambry Genetics
- catecholaminergic polymorphic ventricular tachycardiaInheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen, G2P
- catecholaminergic polymorphic ventricular tachycardia 1Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
- hypertrophic cardiomyopathyInheritance: AD Classification: LIMITED Submitted by: ClinGen
- arrhythmogenic right ventricular cardiomyopathyInheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
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ACMG classification
Our verdict: Likely_pathogenic. The variant received 9 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
RYR2 | ENST00000366574.7 | c.1197G>A | p.Met399Ile | missense_variant | Exon 14 of 105 | 1 | NM_001035.3 | ENSP00000355533.2 | ||
RYR2 | ENST00000661330.2 | c.1197G>A | p.Met399Ile | missense_variant | Exon 14 of 106 | ENSP00000499393.2 | ||||
RYR2 | ENST00000609119.2 | n.1197G>A | non_coding_transcript_exon_variant | Exon 14 of 104 | 5 | ENSP00000499659.2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 30
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not specified Uncertain:1
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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at