ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.2364C>A (p.Phe788Leu)

gnomAD frequency: 0.00001  dbSNP: rs776018906
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV002534365 SCV000827622 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 1 2021-10-15 criteria provided, single submitter clinical testing 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. 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. ClinVar contains an entry for this variant (Variation ID: 576435). This variant has not been reported in the literature in individuals affected with RYR2-related conditions. This variant is present in population databases (rs776018906, ExAC 0.004%). This sequence change replaces phenylalanine with leucine at codon 788 of the RYR2 protein (p.Phe788Leu). The phenylalanine residue is highly conserved and there is a small physicochemical difference between phenylalanine and leucine.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000757729 SCV000886067 uncertain significance not provided 2018-05-18 criteria provided, single submitter clinical testing The p.Phe788Leu variant (rs776018906) has not been reported in the medical literature, gene specific variation databases, nor has it been previously identified by our laboratory. This variant is listed in the Genome Aggregation Database (gnomAD) with an overall population frequency of 0.001 percent (identified on 3 out of 246,232 chromosomes). The phenylalanine at position 788 is highly conserved considering 10 species (Alamut v2.11) and computational analyses of the p.Phe788Leu variant on protein structure and function indicates a deleterious effect (SIFT: damaging, PolyPhen-2: possibly damaging). Altogether, there is not enough evidence to classify the p.Phe788Leu variant with certainty.
Ambry Genetics RCV002442487 SCV002735119 uncertain significance Cardiovascular phenotype 2021-06-21 criteria provided, single submitter clinical testing The p.F788L variant (also known as c.2364C>A), located in coding exon 21 of the RYR2 gene, results from a C to A substitution at nucleotide position 2364. The phenylalanine at codon 788 is replaced by leucine, an amino acid with highly similar properties. 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.

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