Classification and correlation of RYR2 missense variants in individuals with catecholaminergic polymorphic ventricular tachycardia reveals phenotypic relationshipsCitation formats

  • External authors:
  • Damilola Olubando
  • James Eden
  • Richard Caswell
  • N Lowri Thomas

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Classification and correlation of RYR2 missense variants in individuals with catecholaminergic polymorphic ventricular tachycardia reveals phenotypic relationships. / Olubando, Damilola; Hopton, Claire; Eden, James; Caswell, Richard; Thomas, N Lowri; Roberts, Stephen A; Venetucci, Luigi; Newman, William.

In: Journal of Human Genetics, Vol. 65, 10.03.2020, p. 531-539.

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@article{ad66750921cc4632bbb4d893131e8fa1,
title = "Classification and correlation of RYR2 missense variants in individuals with catecholaminergic polymorphic ventricular tachycardia reveals phenotypic relationships",
abstract = "Catecholaminergic polymorphic ventricular tachycardia (CPVT) is predominantly caused by heterozygous missense variants in the cardiac ryanodine receptor, RYR2. However, many RYR2 missense variants are classified as variants of uncertain significance (VUS). We systematically re-evaluated all RYR2 variants in healthy individuals and those with CPVT or arrhythmia using the 2015 American College of Medical Genomics guidelines. RYR2 variants were identified by the NW Genomic Laboratory Hub, from the published literature and databases of sequence variants. Each variant was assessed based on minor allele frequencies, in silico prediction tools and appraisal of functional studies and classified according to the ACMG-AMP guidelines. Phenotype data was collated where available. Of the 326 identified RYR2 missense variants, 55 (16.9%), previously disease-associated variants were re-classified as benign. Application of the gnomAD database of >140,000 controls allowed reclassification of 11 variants more than the ExAC database. CPVT-associated RYR2 variants clustered predominantly between amino acid positions 3949-4332 and 4867-4967 as well as the RyR and IP3R homology associated and ion transport domains (P < 0.005). CPVT-associated RYR2 variants occurred at more conserved amino acid positions compared to controls, and variants associated with sudden death had higher conservation scores (P < 0.005). There were five potentially pathogenic RYR2 variants associated with sudden death during sleep which were located almost exclusively in the C-terminus of the protein. In conclusion, control sequence databases facilitate reclassification of RYR2 variants but the majority remain as VUS. Notably, pathogenic variants in RYR2 are associated with death in sleep.",
author = "Damilola Olubando and Claire Hopton and James Eden and Richard Caswell and Thomas, {N Lowri} and Roberts, {Stephen A} and Luigi Venetucci and William Newman",
year = "2020",
month = mar,
day = "10",
doi = "10.1038/s10038-020-0738-6",
language = "English",
volume = "65",
pages = "531--539",
journal = "Journal of Human Genetics",
issn = "1434-5161",
publisher = "Springer Nature",

}

RIS

TY - JOUR

T1 - Classification and correlation of RYR2 missense variants in individuals with catecholaminergic polymorphic ventricular tachycardia reveals phenotypic relationships

AU - Olubando, Damilola

AU - Hopton, Claire

AU - Eden, James

AU - Caswell, Richard

AU - Thomas, N Lowri

AU - Roberts, Stephen A

AU - Venetucci, Luigi

AU - Newman, William

PY - 2020/3/10

Y1 - 2020/3/10

N2 - Catecholaminergic polymorphic ventricular tachycardia (CPVT) is predominantly caused by heterozygous missense variants in the cardiac ryanodine receptor, RYR2. However, many RYR2 missense variants are classified as variants of uncertain significance (VUS). We systematically re-evaluated all RYR2 variants in healthy individuals and those with CPVT or arrhythmia using the 2015 American College of Medical Genomics guidelines. RYR2 variants were identified by the NW Genomic Laboratory Hub, from the published literature and databases of sequence variants. Each variant was assessed based on minor allele frequencies, in silico prediction tools and appraisal of functional studies and classified according to the ACMG-AMP guidelines. Phenotype data was collated where available. Of the 326 identified RYR2 missense variants, 55 (16.9%), previously disease-associated variants were re-classified as benign. Application of the gnomAD database of >140,000 controls allowed reclassification of 11 variants more than the ExAC database. CPVT-associated RYR2 variants clustered predominantly between amino acid positions 3949-4332 and 4867-4967 as well as the RyR and IP3R homology associated and ion transport domains (P < 0.005). CPVT-associated RYR2 variants occurred at more conserved amino acid positions compared to controls, and variants associated with sudden death had higher conservation scores (P < 0.005). There were five potentially pathogenic RYR2 variants associated with sudden death during sleep which were located almost exclusively in the C-terminus of the protein. In conclusion, control sequence databases facilitate reclassification of RYR2 variants but the majority remain as VUS. Notably, pathogenic variants in RYR2 are associated with death in sleep.

AB - Catecholaminergic polymorphic ventricular tachycardia (CPVT) is predominantly caused by heterozygous missense variants in the cardiac ryanodine receptor, RYR2. However, many RYR2 missense variants are classified as variants of uncertain significance (VUS). We systematically re-evaluated all RYR2 variants in healthy individuals and those with CPVT or arrhythmia using the 2015 American College of Medical Genomics guidelines. RYR2 variants were identified by the NW Genomic Laboratory Hub, from the published literature and databases of sequence variants. Each variant was assessed based on minor allele frequencies, in silico prediction tools and appraisal of functional studies and classified according to the ACMG-AMP guidelines. Phenotype data was collated where available. Of the 326 identified RYR2 missense variants, 55 (16.9%), previously disease-associated variants were re-classified as benign. Application of the gnomAD database of >140,000 controls allowed reclassification of 11 variants more than the ExAC database. CPVT-associated RYR2 variants clustered predominantly between amino acid positions 3949-4332 and 4867-4967 as well as the RyR and IP3R homology associated and ion transport domains (P < 0.005). CPVT-associated RYR2 variants occurred at more conserved amino acid positions compared to controls, and variants associated with sudden death had higher conservation scores (P < 0.005). There were five potentially pathogenic RYR2 variants associated with sudden death during sleep which were located almost exclusively in the C-terminus of the protein. In conclusion, control sequence databases facilitate reclassification of RYR2 variants but the majority remain as VUS. Notably, pathogenic variants in RYR2 are associated with death in sleep.

U2 - 10.1038/s10038-020-0738-6

DO - 10.1038/s10038-020-0738-6

M3 - Article

VL - 65

SP - 531

EP - 539

JO - Journal of Human Genetics

JF - Journal of Human Genetics

SN - 1434-5161

ER -