Submissions for variant NM_001035.3(RYR2):c.7458T>G (p.His2486Gln)

gnomAD frequency: 0.00002  dbSNP: rs377763795

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002537400	SCV000956303	likely benign	Catecholaminergic polymorphic ventricular tachycardia 1	2024-12-20	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001186812	SCV001353393	uncertain significance	Cardiomyopathy	2022-12-02	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with glutamine at codon 2486 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 not been reported in individuals affected with RYR2-related disorders in the literature. This variant has been identified in 3/276152 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.
GeneDx	RCV001797146	SCV002038981	uncertain significance	not provided	2021-12-10	criteria provided, single submitter	clinical testing	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; 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 a patient with sudden arrhythmic death syndrome (SADS) (Raju et al., 2019); however, specific clinical information was not provided; This variant is associated with the following publications: (PMID: 19926015, 31534214, 31337358)
Ambry Genetics	RCV002381830	SCV002674115	uncertain significance	Cardiovascular phenotype	2022-05-09	criteria provided, single submitter	clinical testing	The p.H2486Q variant (also known as c.7458T>G), located in coding exon 49 of the RYR2 gene, results from a T to G substitution at nucleotide position 7458. The histidine at codon 2486 is replaced by glutamine, an amino acid with highly similar properties. This variant has been detected in a sudden death and whole exome sequencing cohorts; however, details were limited (Landstrom AP et al. Circ Arrhythm Electrophysiol, 2017 Apr;10; Raju H et al. BMC Cardiovasc Disord, 2019 Jul;19:174; Lahrouchi N et al. Eur J Hum Genet, 2020 01;28:17-22). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
All of Us Research Program, National Institutes of Health	RCV004001783	SCV004814313	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia	2024-09-23	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with glutamine at codon 2486 of the RYR2 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 3/276152 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004702450	SCV005205306	uncertain significance	not specified	2024-06-04	criteria provided, single submitter	clinical testing	Variant summary: RYR2 c.7458T>G (p.His2486Gln) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.2e-06 in 244748 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.7458T>G has been reported in the literature in individuals affected with sudden cardiac death and in clinical whole exome sequencing cohort (Lahrouchi_2020, Landstrom_2017, Raju_2019). These report(s) 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: 31534214, 28404607, 31337358, 25041964). ClinVar contains an entry for this variant (Variation ID: 658915). Based on the evidence outlined above, the variant was classified as uncertain significance