rs1415931588
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PS1PM1PM2PP2PP3_ModeratePP5_Moderate
The ENST00000366574.7(RYR2):c.567A>T(p.Glu189Asp) variant causes a missense change involving the alteration of a non-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 Likely pathogenic (★). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin ClinVar.
Frequency
Consequence
ENST00000366574.7 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
RYR2 | NM_001035.3 | c.567A>T | p.Glu189Asp | missense_variant | 8/105 | ENST00000366574.7 | NP_001026.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
RYR2 | ENST00000366574.7 | c.567A>T | p.Glu189Asp | missense_variant | 8/105 | 1 | NM_001035.3 | ENSP00000355533 | P1 | |
RYR2 | ENST00000660292.2 | c.567A>T | p.Glu189Asp | missense_variant | 8/106 | ENSP00000499787 | ||||
RYR2 | ENST00000659194.3 | c.567A>T | p.Glu189Asp | missense_variant | 8/105 | ENSP00000499653 | ||||
RYR2 | ENST00000609119.2 | c.567A>T | p.Glu189Asp | missense_variant, NMD_transcript_variant | 8/104 | 5 | ENSP00000499659 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 30
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Catecholaminergic polymorphic ventricular tachycardia 1 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 04, 2017 | In summary, this variant is a rare missense change that has been reported in affected individuals and has been shown to disrupt protein function. This evidence indicates that this variant is pathogenic, but additional data is needed to prove this conclusively. For these reasons, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this missense change enhances the basal activity of RYR2 and increases the fractional calcium release (PMID: 20676041, 22374134). This variant has been reported in the literature in two individuals from one family affected with catecholaminergic polymorphic ventricular tachycardia (CPVT) (PMID: 20676041), and in at least one other unrelated affected individual (PMID: 19926015, Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamic acid with aspartic acid at codon 189 of the RYR2 protein (p.Glu189Asp). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and aspartic acid. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at