rs1060503778
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PM2
The NM_001035.3(RYR2):βc.10033delβ(p.Arg3345GlyfsTer12) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,613,556 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (β β ). Synonymous variant affecting the same amino acid position (i.e. R3345R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_001035.3 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RYR2 | NM_001035.3 | c.10033del | p.Arg3345GlyfsTer12 | frameshift_variant | 69/105 | ENST00000366574.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RYR2 | ENST00000366574.7 | c.10033del | p.Arg3345GlyfsTer12 | frameshift_variant | 69/105 | 1 | NM_001035.3 | P1 | |
RYR2 | ENST00000660292.2 | c.10033del | p.Arg3345GlyfsTer12 | frameshift_variant | 69/106 | ||||
RYR2 | ENST00000659194.3 | c.10033del | p.Arg3345GlyfsTer12 | frameshift_variant | 69/105 | ||||
RYR2 | ENST00000609119.2 | c.*1068del | 3_prime_UTR_variant, NMD_transcript_variant | 67/104 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 152048Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000402 AC: 1AN: 248808Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 134998
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461508Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 727032
GnomAD4 genome ? AF: 0.00000658 AC: 1AN: 152048Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74272
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 01, 2019 | Has not been previously published as pathogenic or benign to our knowledge; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is not a known mechanism of disease; Reported in ClinVar but additional evidence is not available (ClinVar Variant ID 412517; Landrum et al., 2016) - |
Uncertain significance, criteria provided, single submitter | clinical testing | AiLife Diagnostics, AiLife Diagnostics | Dec 30, 2021 | - - |
Catecholaminergic polymorphic ventricular tachycardia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jan 03, 2024 | This variant deletes 1 nucleotide in exon 69 of the RYR2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, this variant has not been reported in individuals affected with RYR2-related disorders in the literature. This variant has been identified in 1/248808 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Clinical relevance of loss-of-function RYR2 variants in autosomal dominant cardiovascular disorders is not clearly established. The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Catecholaminergic polymorphic ventricular tachycardia 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 23, 2023 | This sequence change creates a premature translational stop signal (p.Arg3345Glyfs*12) in the RYR2 gene. It is expected to result in an absent or disrupted protein product. However, the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in RYR2 cause disease. This variant is present in population databases (no rsID available, gnomAD 0.0009%). 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: 412517). 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 | Mar 30, 2021 | Loss of function has not been clearly established as a mechanism of disease Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at