ClinVar Genomic variation as it relates to human health

Identified in at least two unrelated individuals with sudden arrhythmic death syndrome (SADS) in the published literature (Lahrouchi et al., 2017; Raju et al., 2019) and in individuals referred for cardiac arrhythmia genetic testing at GeneDx; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; 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); This variant is associated with the following publications: (PMID: 28404607, 31337358, 28449774)

This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 153 of the RYR2 protein (p.Thr153Ile). This variant is present in population databases (rs766802574, gnomAD 0.004%). This missense change has been observed in individual(s) with sudden arrhythmic death syndrome (PMID: 28449774). ClinVar contains an entry for this variant (Variation ID: 201192). 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 not expected to disrupt RYR2 protein function with a negative predictive value of 95%. 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.

This missense variant replaces threonine with isoleucine at codon 153 of the RYR2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a few individuals affected with sudden arrhythmic death syndrome (PMID: 28449774, 31337358). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). 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.

Variant summary: RYR2 c.458C>T (p.Thr153Ile) results in a non-conservative amino acid change located in the MIR domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 244972 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.458C>T has been reported in the literature in individuals affected with Sudden Arrhythmic Death Syndrome or related disorders (e.g. Laurouchi_2017, Raju_2019). These reports do not provide unequivocal conclusions about association of the variant with Catecholaminergic Polymorphic Ventricular Tachycardia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 28404607, 28449774, 31337358). ClinVar contains an entry for this variant (Variation ID: 201192). Based on the evidence outlined above, the variant was classified as uncertain significance.

The p.T153I variant (also known as c.458C>T), located in coding exon 7 of the RYR2 gene, results from a C to T substitution at nucleotide position 458. The threonine at codon 153 is replaced by isoleucine, an amino acid with similar properties. This variant has been detected in individuals from sudden arrhythmic death syndrome cohorts (Lahrouchi N et al. J Am Coll Cardiol, 2017 May;69:2134-2145; Raju H et al. BMC Cardiovasc Disord, 2019 07;19:174; Kotta MC et al. J Am Heart Assoc, 2023 Sep;12:e029100). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.

This missense variant replaces threonine with isoleucine at codon 153 of the RYR2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a few individuals affected with sudden arrhythmic death syndrome (PMID: 28449774, 31337358). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). 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.