Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000182843 | SCV000235231 | pathogenic | not provided | 2014-05-05 | criteria provided, single submitter | clinical testing | p.Lys4751Gln (AAG>CAG): c.14251 A>C in exon 99 of the RYR2 gene (NM_001035.2). The K4751Q mutation in the RYR2 gene has been reported in one Japanese individual diagnosed with CPVT and atrial flutter (Kawamura M et al., 2013). K4751Q is a semi-conservative amino acid substitution as these residues share similar properties, but differs in size, charge, or other properties which may impact secondary structure. K4751Q occurs at a position that is conserved across species and is located in the channel region, which is a known hotspot for mutations (Medeiros-Domingo A et al, 2009). Mutations in nearby residues (H4742Y, H4762P) have been reported in association with sudden cardiac death and CPVT, respectively, further supporting the functional importance of this region of the protein. In silico analysis predicts that K4751Q is probably damaging to protein structure/function. Additionally, the K4751Q mutation was not observed inapproximately 6000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In summary, K4751Q in the RYR2 gene is interpreted as a disease-causing mutation. The variant is found in CPVT panel(s). |
| Ambry Genetics | RCV000621431 | SCV000737686 | likely pathogenic | Cardiovascular phenotype | 2017-12-08 | criteria provided, single submitter | clinical testing | The p.K4751Q variant (also known as c.14251A>C), located in coding exon 99 of the RYR2 gene, results from an A to C substitution at nucleotide position 14251. The lysine at codon 4751 is replaced by glutamine, an amino acid with similar properties. This alteration (reported as c.14251A>C, p.K4750Q) has been previously reported as de novo in an individual with a clinical diagnosis of catecholaminergic polymorphic ventricular tachycardia (CPVT) (Kawamura M et al. Circ J. 2013;77:1705-13; Uehara A et al. J. Gen. Physiol., 2017 Feb;149:199-218). Limited in vitro functional studies demonstrated effects on gating kinetics in transfected cells (Uehara A et al. J. Gen. Physiol., 2017 Feb;149:199-218). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |