rs121918597
Variant summary
Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2PP2PP3_StrongPP5_Very_Strong
The NM_001035.3(RYR2):c.6737C>T(p.Ser2246Leu) 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. S2246S) has been classified as Likely benign.
Frequency
Consequence
NM_001035.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 15 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RYR2 | NM_001035.3 | c.6737C>T | p.Ser2246Leu | missense_variant | 44/105 | ENST00000366574.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RYR2 | ENST00000366574.7 | c.6737C>T | p.Ser2246Leu | missense_variant | 44/105 | 1 | NM_001035.3 | P1 | |
RYR2 | ENST00000660292.2 | c.6737C>T | p.Ser2246Leu | missense_variant | 44/106 | ||||
RYR2 | ENST00000659194.3 | c.6737C>T | p.Ser2246Leu | missense_variant | 44/105 | ||||
RYR2 | ENST00000609119.2 | c.6737C>T | p.Ser2246Leu | missense_variant, NMD_transcript_variant | 44/104 | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 30
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Catecholaminergic polymorphic ventricular tachycardia 1 Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 02, 2002 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 17, 2023 | For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects RYR2 function (PMID: 12837242, 16239587, 18092949, 19226252, 21768539). 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. ClinVar contains an entry for this variant (Variation ID: 12954). This missense change has been observed in individual(s) with catecholaminergic polymorphic ventricular tachycardia (CPVT) (PMID: 11208676, 16843546, 19926015, 23595086, 26114861). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 2246 of the RYR2 protein (p.Ser2246Leu). - |
Cardiomyopathy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Jan 20, 2020 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 26, 2021 | Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate a damaging effect by causing abnormal channel function (Wehrens et al., 2003; Jiang et al., 2005; Suetomi et al., 2011); Is located in one of the three hot-spot regions of the RYR2 gene, where the majority of pathogenic missense variants occur (Medeiros-Domingo et al., 2009); Reported in ClinVar as a pathogenic variant (ClinVar Variant ID# 12954; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 27114410, 18092949, 16843546, 30403697, 31112425, 30640888, 19226252, 12837242, 21768539, 11208676, 15544015, 24025405, 19926015, 26114861, 12919952, 29427818, 28202948, 12093772, 29434162, 29453248, 29453246, 30975432, 30302938, 31995186, 23595086, 16239587, 26582918) - |
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | May 04, 2023 | The p.S2246L pathogenic mutation (also known as c.6737C>T), located in coding exon 44 of the RYR2 gene, results from a C to T substitution at nucleotide position 6737. The serine at codon 2246 is replaced by leucine, an amino acid with dissimilar properties. This mutation has been reported in several unrelated individuals reported to have catecholaminergic polymorphic ventricular tachycardia (CPVT), features of CPVT, or sudden arrest/death, including several cases in whom this mutation occurred de novo (Priori SG et al. Circulation, 2001 Jan;103:196-2001; Priori SG et al. Circulation, 2002 Jul;106:69-74; Aizawa Y et al. Int J Cardiol, 2007 Mar;116:263-5; Ohno S et al. PLoS One, 2015 Jun;10:e0131517; Halvorsen M et al. Proc Natl Acad Sci U S A, 2021 Dec;118; Anderson JH et al. Circ Cardiovasc Genet, 2016 Jun;9:259-65; Song JS et al. J Hum Genet, 2017 Jun;62:615-620; Roston TM et al. PLoS One, 2018 Nov;13:e0205925; Kawamura M et al. Circ J, 2013 Apr;77:1705-13; Chiu SN et al. Arch Dis Child, 2022 Jan;107:41-46; Eitoku T et al. HeartRhythm Case Rep, 2023 Mar;9:152-155). In vitro studies indicate this variant impacts protein function by way of increased calcium sensitivity (Wehrens XH et al. Cell, 2003 Jun;113:829-40; Jones PP et al. Biochem J, 2008 May;412:171-8). Furthermore, a knock-in mouse model expressing this variant recapitulated CPVT phenotype (Suetomi T et al. Circulation, 2011 Aug;124:682-94). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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 supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at