1-237503465-C-T
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4BP6BS2
The NM_001035.3(RYR2):c.2573C>T(p.Thr858Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000694 in 1,613,780 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T858K) 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_benign. Variant got -5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RYR2 | NM_001035.3 | c.2573C>T | p.Thr858Met | missense_variant | 22/105 | ENST00000366574.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RYR2 | ENST00000366574.7 | c.2573C>T | p.Thr858Met | missense_variant | 22/105 | 1 | NM_001035.3 | P1 | |
RYR2 | ENST00000660292.2 | c.2573C>T | p.Thr858Met | missense_variant | 22/106 | ||||
RYR2 | ENST00000659194.3 | c.2573C>T | p.Thr858Met | missense_variant | 22/105 | ||||
RYR2 | ENST00000609119.2 | c.2573C>T | p.Thr858Met | missense_variant, NMD_transcript_variant | 22/104 | 5 |
Frequencies
GnomAD3 genomes AF: 0.0000658 AC: 10AN: 152084Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000441 AC: 11AN: 249268Hom.: 0 AF XY: 0.0000444 AC XY: 6AN XY: 135234
GnomAD4 exome AF: 0.0000698 AC: 102AN: 1461696Hom.: 0 Cov.: 31 AF XY: 0.0000701 AC XY: 51AN XY: 727128
GnomAD4 genome AF: 0.0000658 AC: 10AN: 152084Hom.: 0 Cov.: 32 AF XY: 0.0000539 AC XY: 4AN XY: 74274
ClinVar
Submissions by phenotype
Catecholaminergic polymorphic ventricular tachycardia 1;C1832931:Arrhythmogenic right ventricular dysplasia 2;C5542154:Ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jan 24, 2022 | - - |
Hypertrophic cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Human Genetics, University of Leuven | Oct 31, 2018 | - - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 26, 2022 | The p.T858M variant (also known as c.2573C>T), located in coding exon 22 of the RYR2 gene, results from a C to T substitution at nucleotide position 2573. The threonine at codon 858 is replaced by methionine, an amino acid with similar properties. This alteration has been reported in whole exome sequencing and hypertrophic cardiomyopathy cohorts (Landstrom AP et al. Circ Arrhythm Electrophysiol, 2017 Apr;10; Robyns T et al. Eur J Med Genet, 2020 Mar;63:103754). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Sudden death Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital | Jun 16, 2017 | - - |
Cardiomyopathy Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Feb 28, 2023 | - - |
Catecholaminergic polymorphic ventricular tachycardia 1 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Aug 19, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at