Submissions for variant NM_001035.3(RYR2):c.14302G>A (p.Val4768Ile)

gnomAD frequency: 0.00001  dbSNP: rs775534249

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV002547150	SCV000818143	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 1	2023-12-12	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 4768 of the RYR2 protein (p.Val4768Ile). This variant is present in population databases (rs775534249, gnomAD 0.003%). This missense change has been observed in individual(s) with catecholaminergic polymorphic ventricular tachycardia (PMID: 34546463). ClinVar contains an entry for this variant (Variation ID: 569751). 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000768791	SCV000900163	uncertain significance	Cardiomyopathy	2015-10-29	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000768791	SCV001359125	uncertain significance	Cardiomyopathy	2023-03-09	criteria provided, single submitter	clinical testing	This missense variant replaces valine with isoleucine at codon 4768 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 cardiovascular disorders in the literature. This variant has been identified in 4/249196 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	RCV002388227	SCV002701039	uncertain significance	Cardiovascular phenotype	2022-05-03	criteria provided, single submitter	clinical testing	The p.V4768I variant (also known as c.14302G>A), located in coding exon 100 of the RYR2 gene, results from a G to A substitution at nucleotide position 14302. The valine at codon 4768 is replaced by isoleucine, an amino acid with highly similar properties. This alteration has been reported in an inherited channelopathy cohort (Sarquella-Brugada G et al. Hum Genet, 2021 Sep;[ePub ahead of print]). This amino acid position is well 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.