rs397516508
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PM5PP2PP3_ModeratePP5_Very_Strong
The NM_001035.3(RYR2):c.12544G>C(p.Glu4182Gln) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E4182A) has been classified as Likely pathogenic.
Frequency
Consequence
NM_001035.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 17 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RYR2 | NM_001035.3 | c.12544G>C | p.Glu4182Gln | missense_variant | 90/105 | ENST00000366574.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RYR2 | ENST00000366574.7 | c.12544G>C | p.Glu4182Gln | missense_variant | 90/105 | 1 | NM_001035.3 | P1 | |
RYR2 | ENST00000660292.2 | c.12565G>C | p.Glu4189Gln | missense_variant | 91/106 | ||||
RYR2 | ENST00000659194.3 | c.12532G>C | p.Glu4178Gln | missense_variant | 90/105 | ||||
RYR2 | ENST00000609119.2 | c.*3636G>C | 3_prime_UTR_variant, NMD_transcript_variant | 89/104 | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 33
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Catecholaminergic polymorphic ventricular tachycardia Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 26, 2013 | The Glu4182Gln variant in RYR2 has been identified by our laboratory in 1 Caucas ian child with CPVT, where it occurred de novo. This variant has not been seen i n large population studies. Computational analyses (biochemical amino acid prope rties, conservation, AlignGVGD, PolyPhen2, and SIFT) suggest that the Glu4182Gln variant may impact the protein, though this information is not predictive enoug h to determine pathogenicity. In summary, all available data supports that the Glu4182Gln variant is likely pathogenic, but additional studies are needed to fu lly assess its clinical significance. - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 27, 2013 | p.Glu4182Gln (GAG>CAG): c.12544 G>C in exon 90 of the RYR2 gene (NM_001035.2). The Glu4182Gln variant in the RYR2 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. The Glu4182Gln variant is a semi-conservative amino acid substitution as these residues share similar properties, but differ in size, charge, or other properties which may impact secondary structure. However, the Glu4182Gln residue is conserved across species. In silico analysis predicts Glu4182Gln is probably damaging to the protein structure/function. Mutations in nearby residues (Asn4178Tyr, Asn4178Ser, Glu4187Gln, and Leu4188Pro) have been reported in association with CPVT, further supporting the functional importance of this region of the protein. Glu4182Gln is located in the channel region, a mutation hotspot region of the RYR2 gene (Medeiros- Domingo A et al., 2009). Furthermore, the Glu4182Gln variant was not observed in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In summary, while Glu4182Gln is a good candidate for a disease-causing mutation, we cannot unequivocally determine the clinical significance of this variant. The variant is found in CPVT panel(s). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at