Submissions for variant NM_001035.3(RYR2):c.12152C>T (p.Ala4051Val)

gnomAD frequency: 0.00001  dbSNP: rs1326672128

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002550026	SCV001558250	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 1	2023-11-22	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 4051 of the RYR2 protein (p.Ala4051Val). This variant is present in population databases (no rsID available, gnomAD 0.002%). This missense change has been observed in individual(s) with sudden death (PMID: 28449774). ClinVar contains an entry for this variant (Variation ID: 1053844). 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.
GeneDx	RCV001551386	SCV001771881	uncertain significance	not provided	2021-04-01	criteria provided, single submitter	clinical testing	Reported in a male with sudden arrhythmic death syndrome (SADS), who died during sleep at 13 years of age and had a previous history of seizures (Lahrouchi et al., 2017); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; 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: 28449774)
Ambry Genetics	RCV002357231	SCV002654887	uncertain significance	Cardiovascular phenotype	2021-06-22	criteria provided, single submitter	clinical testing	The p.A4051V variant (also known as c.12152C>T), located in coding exon 90 of the RYR2 gene, results from a C to T substitution at nucleotide position 12152. The alanine at codon 4051 is replaced by valine, an amino acid with similar properties. This alteration has been reported in sudden cardiac death cohort (Lahrouchi N et al. J. Am. Coll. Cardiol., 2017 May;69:2134-2145). This amino acid position is highly conserved in available vertebrate species; however, valine is the reference amino acid in other 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	RCV004005286	SCV004819632	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia	2023-03-09	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with valine at codon 4051 of the RYR2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with sudden arrhythmic death syndrome (PMID: 28449774). This variant has been identified in 2/279622 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.