Submissions for variant NM_001035.3(RYR2):c.3767C>T (p.Pro1256Leu)

gnomAD frequency: 0.00001  dbSNP: rs773915323

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001176899	SCV001340997	uncertain significance	Cardiomyopathy	2023-01-03	criteria provided, single submitter	clinical testing	This variant is located in 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 been reported in an individual affected with Wolff-Parkinson-White syndrome, a relatively common arrhythmia (PMID: 32233023). This variant has been identified in 5/280366 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003153749	SCV001509709	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 1	2021-08-27	criteria provided, single submitter	clinical testing	This sequence change replaces proline with leucine at codon 1256 of the RYR2 protein (p.Pro1256Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs773915323, ExAC 0.003%). This variant has not been reported in the literature in individuals affected with RYR2-related conditions. ClinVar contains an entry for this variant (Variation ID: 487620). 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 expected to disrupt RYR2 protein function. 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.
Ambry Genetics	RCV002367975	SCV002625953	uncertain significance	Cardiovascular phenotype	2021-07-22	criteria provided, single submitter	clinical testing	The p.P1256L variant (also known as c.3767C>T), located in coding exon 30 of the RYR2 gene, results from a C to T substitution at nucleotide position 3767. The proline at codon 1256 is replaced by leucine, an amino acid with similar properties. This amino acid position is well 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.
Fulgent Genetics, Fulgent Genetics	RCV002506386	SCV002816830	uncertain significance	Arrhythmogenic right ventricular dysplasia 2; Catecholaminergic polymorphic ventricular tachycardia 1; Ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome	2021-11-24	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004001213	SCV004819261	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia	2023-08-15	criteria provided, single submitter	clinical testing	This variant is located in 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 been reported in an individual affected with Wolff-Parkinson-White syndrome, a relatively common arrhythmia (PMID: 32233023). This variant has been identified in 5/280366 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.
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	RCV000656197	SCV000678391	uncertain significance	Wolff-Parkinson-White pattern	2017-07-14	no assertion criteria provided	research	This variant was identified in an individual with Wolff-Parkinson-White syndrome