Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV002544779 | SCV000815103 | uncertain significance | Catecholaminergic polymorphic ventricular tachycardia 1 | 2023-08-03 | criteria provided, single submitter | clinical testing | 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. Experimental studies have shown that this missense change affects RYR2 function (PMID: 15364613). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 567443). This missense change has been observed in individual(s) with clinical features of RYR2-related conditions (PMID: 11159936, 12106942, 24978818, 28416588). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 2504 of the RYR2 protein (p.Thr2504Met). |
| Color Diagnostics, |
RCV001805802 | SCV002052151 | uncertain significance | Cardiomyopathy | 2023-04-03 | criteria provided, single submitter | clinical testing | This missense variant replaces threonine with methionine at codon 2504 of the RYR2 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown that this variant changes calcium channel activities (PMID: 15364613). This variant has been reported in a family affected with arrhythmogenic right ventricular dysplasia type 2 including three affected individuals who also carried another pathogenic RYR2 variant (PMID: 11159936). This variant has also been reported in two related individuals affected with polymorphic ventricular arrhythmia (PMID: 12106942) as well as in three unaffected family members. Additionally, this variant has been reported in an individual affected with idiopathic ventricular tachycardia (PMID: 24978818) and in an individual affected with dilated cardiomyopathy (PMID: 28416588). This variant has been identified in 13/269360 chromosomes 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. |
| Ambry Genetics | RCV002388207 | SCV002672645 | uncertain significance | Cardiovascular phenotype | 2023-03-17 | criteria provided, single submitter | clinical testing | The p.T2504M variant (also known as c.7511C>T), located in coding exon 49 of the RYR2 gene, results from a C to T substitution at nucleotide position 7511. The threonine at codon 2504 is replaced by methionine, an amino acid with similar properties. This variant co-occurred with an RYR2 pathogenic variant in a family reported to have arrhythmogenic right ventricular cardiomyopathy (Bauce B et al. Am J Cardiol, 2000 Mar;85:573-9; Tiso N et al. Hum Mol Genet, 2001 Feb;10:189-94). This variant has been seen in an individual with idiopathic ventricular tachycardia, and was also seen in two individuals with arrhythmia from a family in which five unaffected relatives carried the variant (Bauce B et al. J Am Coll Cardiol, 2002 Jul;40:341-9; Akilzhanova A et al. PLoS One, 2014 Jun;9:e101059). This variant has also been detected in a dilated cardiomyopathy cohort and in a cohort with developmental disorders; however, details were limited (Dal Ferro M et al. Heart, 2017 11;103:1704-1710; Mcrae et al. Nature, 2017 02;542:433-438). This variant and the double mutant p.T2504M/p.R176Q have been reported to impact protein function in in vitro assays; however, the physiological relevance in the context of p.T2504M alone is unclear (Thomas NL. Cardiovasc Res. 2004 Oct;64(1):52-60). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003323686 | SCV004028837 | likely benign | not specified | 2023-07-15 | criteria provided, single submitter | clinical testing | Variant summary: RYR2 c.7511C>T (p.Thr2504Met) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. As the variant alters the penultimate nucleotide of exon 49 located in the exonic splice region near the canonical intron 49 splice donor site, several computational tools predict a significant impact on normal splicing: Three predict the variant weakens the canonical 5' splicing donor site, while one predict the variant no significant impact on splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4.2e-05 in 237960 control chromosomes. The observed variant frequency is approximately 1.2 fold of the estimated maximal expected allele frequency for a pathogenic variant in RYR2 causing Catecholaminergic Polymorphic Ventricular Tachycardia phenotype (3.4e-05), strongly suggesting that the variant is benign. c.7511C>T has been reported in the literature in a variety of cardiac conditions, such as, 1. co-occurring with a different pathogenic RYR2 variant (p.Arg176Gln) in affected family members from a single family affected with arrhythmogenic right ventricular cardiomyopathy type 2 (ARVD2) (Tiso_2001), 2. in affected and unaffected family members of a family affected with ventricular tachycardias (Bauce_2002); 3. an individual with idopathic ventricular tachycardia (IVT) (Akilzhanova_2014) and 4. an individual with dilated cardiomyopathy (DCM) (Dal Ferro_2017). Since the penetrance due to this variant appears to be lower than expected, no conclusions can be drawn from these data. At-least one co-occurrence with another pathogenic variant has been reported (Tiso_2001, RYR2 c.527G>A, p.Arg176Gln), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect in isolation (Thomas_2004). At-least two recent studies have categorized this variant as "benign" (Olubando_2020, Guelly_2021). The following publications have been ascertained in the context of this evaluation (PMID: 24978818, 12106942, 28416588, 33552729, 32152366, 15364613, 11159936). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance citing overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely benign. |