rs397516544
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PM5PP2PP3_Moderate
The NM_001035.3(RYR2):c.570G>T(p.Arg190Ser) 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R190K) has been classified as Uncertain significance.
Frequency
Consequence
NM_001035.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RYR2 | NM_001035.3 | c.570G>T | p.Arg190Ser | missense_variant | 8/105 | ENST00000366574.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RYR2 | ENST00000366574.7 | c.570G>T | p.Arg190Ser | missense_variant | 8/105 | 1 | NM_001035.3 | P1 | |
RYR2 | ENST00000660292.2 | c.570G>T | p.Arg190Ser | missense_variant | 8/106 | ||||
RYR2 | ENST00000659194.3 | c.570G>T | p.Arg190Ser | missense_variant | 8/105 | ||||
RYR2 | ENST00000609119.2 | c.570G>T | p.Arg190Ser | missense_variant, NMD_transcript_variant | 8/104 | 5 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 29
GnomAD4 genome Cov.: 32
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 | Feb 02, 2012 | Variant classified as Uncertain Significance - Favor Pathogenic. The Arg190Ser v ariant (RYR2) has not been reported in the literature nor previously identified by our laboratory. Arginine (Arg) at position 190 is highly conserved in mammal s and across evolutionarily distant species, suggesting that a change would not be tolerated. Computational analyses (biochemical amino acid properties, AlignGV GD, PolyPhen2, and SIFT) suggest that the Arg190Ser variant may impact the prote in, though this information is not predictive enough to determine pathogenicity. Therefore, the clinical significance of this variant cannot be determined with certainty at this time. - |
Catecholaminergic polymorphic ventricular tachycardia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 23, 2021 | This sequence change replaces arginine with serine at codon 190 of the RYR2 protein (p.Arg190Ser). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and serine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with RYR2-related conditions. ClinVar contains an entry for this variant (Variation ID: 43808). 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 expected to disrupt RYR2 protein function. 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at