Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV002527801 | SCV000637525 | pathogenic | Catecholaminergic polymorphic ventricular tachycardia 1 | 2022-03-19 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 463577). This missense change has been observed in individual(s) with clinical features of RYR2-related conditions (Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 4751 of the RYR2 protein (p.Lys4751Glu). |
| Stanford Center for Inherited Cardiovascular Disease, |
RCV000786201 | SCV000924917 | likely pathogenic | not provided | 2017-06-08 | no assertion criteria provided | provider interpretation | We consider the c.14251A>G (p.Lys4751Glu; p.K4751E) variant to be Likely Pathogenic, as it is present de novo in our affected patient and not present in his unaffected parents. The variant is absent from the gnomAD population dataset, despite reports of good sequencing coverage at this site. gnomAD (http://gnomad.broadinstitute.org) includes variant calls from 123,136 exome sequences and 15,496 genome sequences from unrelated individuals of non-Finnish European, Finnish, African, Latino, Ashkenazi Jewish, East Asian, and South Asian descent. gnomAD is comprised of multiple cohorts, some of which were recruited from the general population and others that include individuals sequenced as part of various disease-specific and population genetic studies; the phenotypes of individuals are not publicly available. The p.Lys4751Glu variant is novel. It has not been reported to date in the literature in any individuals with a RYR2-related disease, and it has not been submitted to ClinVar. However, a different variant at this same residue (p.Lys4751Gln; p.K4751Q) has been reported in one Japanese individual diagnosed with CPVT and atrial flutter (Kawamura et al., 2013). In ClinVar, the p.Lys4751Gln variant is classified as pathogenic by GeneDx as of 5/5/2014. In silico analysis programs (including PolyPhen, SIFT and MutationTaster) predict the p.Lys4751Glu variant to be damaging. The variant occurs at a residue that is highly conserved across vertebrate species and it is located in the channel region of the RYR2 gene, which is a known hotspot for mutations (Medeiros-Domingo A et al, 2009). Variants in nearby residues (p.His4742Tyr, p.His4762Pro) have been reported in the literature in association with sudden cardiac death and CPVT, respectively. Furthermore, variants in nearby residues (p.Val4760Ile, p.Asn4763Ser) have been reported to ClinVar as Likely Pathogenic, supporting the functional importance of this region of the protein. In summary, we consider this variant to be a rare missense change that is likely pathogenic. |