chr1-237377365-G-T
Variant summary
Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_001035.3(RYR2):c.506G>T(p.Arg169Leu) 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. R169Q) 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 19 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
RYR2 | ENST00000366574.7 | c.506G>T | p.Arg169Leu | missense_variant | Exon 8 of 105 | 1 | NM_001035.3 | ENSP00000355533.2 | ||
RYR2 | ENST00000609119.2 | n.506G>T | non_coding_transcript_exon_variant | Exon 8 of 104 | 5 | ENSP00000499659.2 | ||||
RYR2 | ENST00000660292.2 | c.506G>T | p.Arg169Leu | missense_variant | Exon 8 of 106 | ENSP00000499787.2 | ||||
RYR2 | ENST00000659194.3 | c.506G>T | p.Arg169Leu | missense_variant | Exon 8 of 105 | ENSP00000499653.3 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:1
While the R169L variant in the RYR2 gene has not been reported to our knowledge, a pathogenic variant affectingthis same residue, R169Q, has been reported in association with exercised induced ventricular tachycardiaand was absent in 100 reference alleles (Hsueh C et al., 2006). Additionally, variants in nearby residues(P164S, A165D, R176Q) have been reported in HGMD in association with polymorphic ventriculartachycardia and arrhythmogenic right ventricular dysplasia type 2 (Stenson P et al., 2014). Furthermore,R169L is located in one of the three hot-spot regions of the RYR2 gene, where the majority of pathogenicmissense variants occur (Medeiros-Domingo et al., 2009). R169L results in a non-conservative amino acid substitution at a position that is conserved across species. In silico analysis predicts is damaging to theprotein structure/function. Finally, the R169L variant was not observed in approximately 6100 individualsof European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is nota common benign variant in these populations. In summary, R169L in the RYR2 gene is interpreted as a pathogenic variant. -
Cardiovascular phenotype Pathogenic:1
The p.R169L variant (also known as c.506G>T), located in coding exon 8 of the RYR2 gene, results from a G to T substitution at nucleotide position 506. The arginine at codon 169 is replaced by leucine, an amino acid with dissimilar properties. This variant was reported as de novo in one individual with a history of syncope, who was part of a catecholaminergic polymorphic ventricular tachycardia (CPVT) testing cohort (Ohno S et al. PLoS ONE, 2015 Jun;10:e0131517). An alternate amino acid substitution at this position, p.R169Q, has also been reported in CPVT cohorts, including two apparently de novo cases (Hsueh CH et al. Int J Cardiol. 2006;108:276-8; Ohno S et al. PLoS ONE, 2015 Jun;10:e0131517). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at