rs1036775644
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP2BP4
The NM_001035.3(RYR2):c.11132T>A(p.Val3711Glu) variant causes a missense change. The variant allele was found at a frequency of 0.0000264 in 151,292 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V3711M) has been classified as Likely benign.
Frequency
Consequence
NM_001035.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RYR2 | NM_001035.3 | c.11132T>A | p.Val3711Glu | missense_variant | 80/105 | ENST00000366574.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RYR2 | ENST00000366574.7 | c.11132T>A | p.Val3711Glu | missense_variant | 80/105 | 1 | NM_001035.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000264 AC: 4AN: 151292Hom.: 0 Cov.: 32
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1416678Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0AN XY: 701672
GnomAD4 genome ? AF: 0.0000264 AC: 4AN: 151292Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 73804
ClinVar
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | May 27, 2016 | The p.Val3711Glu variant in RYR2 has not been previously reported in individuals with cardiomyopathy or in large population studies. Computational prediction to ols and conservation analysis do not provide strong support for or against an im pact to the protein. In summary, the clinical significance of the p.Val3711Glu v ariant is uncertain. - |
Catecholaminergic polymorphic ventricular tachycardia 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 11, 2023 | This sequence change replaces valine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 3711 of the RYR2 protein (p.Val3711Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with left ventricular noncompaction (PMID: 33500567). ClinVar contains an entry for this variant (Variation ID: 505023). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt RYR2 protein function with a negative predictive value of 95%. 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. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 31, 2022 | The p.V3711E variant (also known as c.11132T>A), located in coding exon 80 of the RYR2 gene, results from a T to A substitution at nucleotide position 11132. The valine at codon 3711 is replaced by glutamic acid, an amino acid with dissimilar properties. This alteration has been reported in a left ventricular non-compaction (LVNC) cohort; however, clinical details were limited (Mazzarotto F et al. Genet Med, 2021 05;23:856-864). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at