Submissions for variant NM_001035.3(RYR2):c.8147A>T (p.Lys2716Ile)

gnomAD frequency: 0.00005  dbSNP: rs749618476

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000724224	SCV000231340	uncertain significance	not provided	2014-11-15	criteria provided, single submitter	clinical testing
Invitae	RCV002515274	SCV000285750	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 1	2022-10-30	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with isoleucine, which is neutral and non-polar, at codon 2716 of the RYR2 protein (p.Lys2716Ile). This variant is present in population databases (rs749618476, gnomAD 0.01%). This missense change has been observed in individual(s) with unspecified arrhythmia (PMID: 30847666). ClinVar contains an entry for this variant (Variation ID: 197961). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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.
GeneDx	RCV000724224	SCV000576742	uncertain significance	not provided	2023-08-03	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28404607, 30847666)
CeGaT Center for Human Genetics Tuebingen	RCV000724224	SCV001147765	uncertain significance	not provided	2019-05-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001176808	SCV001340866	uncertain significance	Cardiomyopathy	2022-12-09	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with isoleucine at codon 2716 of the RYR2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 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 cardiovascular disorders in the literature. This variant has been identified in 6/135176 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	RCV002415766	SCV002680328	uncertain significance	Cardiovascular phenotype	2022-06-21	criteria provided, single submitter	clinical testing	The p.K2716I variant (also known as c.8147A>T), located in coding exon 54 of the RYR2 gene, results from an A to T substitution at nucleotide position 8147. The lysine at codon 2716 is replaced by isoleucine, an amino acid with dissimilar properties. This variant has been detected in an exome sequencing cohort, and in a non-compaction cardiomyopathy cohort; however, clinical details were limited (Landstrom AP et al. Circ Arrhythm Electrophysiol, 2017 Apr;10; van Waning JI et al. J. Am. Coll. Cardiol., 2018 Feb;71:711-722). This alteration was also reported in a family with dilated cardiomyopathy and left bundle branch block who also carried an alteration in LMNA (Hoorntje ET et al. Circ Cardiovasc Genet, 2017 Aug;10:). This variant was also detected in a cardiomyopathy/arrhythmia genetic testing cohort; however, clinical details were limited, and additional cardiac variants were detected in some cases (van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000724224	SCV001742981	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000724224	SCV001919406	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000724224	SCV001963733	uncertain significance	not provided		no assertion criteria provided	clinical testing