Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Laboratory for Molecular Medicine, |
RCV000038188 | SCV000061855 | uncertain significance | not specified | 2011-03-15 | criteria provided, single submitter | clinical testing | Variant classified as Uncertain Significance - Favor Benign. The Ile630Thr varia nt has not been reported in the literature. It has been detected in 1/200 Caucas ian probands tested by our laboratory. This proband had dilated cardiomyopathy a nd carried a second variant in the MYH7 gene, which precludes an assessment of t he possible contribution of the Ile630Thr variant to disease. (Isoleucine (Ile) at position 630 is incompletely conserved in evolution (of the available species , opossum and zebrafish carry a different amino acid), raising the possibility t hat a change may be tolerated. In addition, 3 out of 4 computational tools (Alig n GVGD, SIFT, MAPP) predict the change to be tolerated (Polyphen2 predicts a pos sibly damaging effect). Finally, missense variants constitute the minority of va riants detected in ARVC patients (23% in our laboratory) and their clinical sign ificance has been questioned by some (Christensen 2009). In summary, additional studies are needed to determine the clinical significance of this variant. |
| Invitae | RCV000457220 | SCV000545233 | uncertain significance | Arrhythmogenic right ventricular dysplasia 9 | 2023-02-23 | criteria provided, single submitter | clinical testing | This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 630 of the PKP2 protein (p.Ile630Thr). This variant is present in population databases (rs397517011, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with PKP2-related conditions. ClinVar contains an entry for this variant (Variation ID: 45048). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant  is likely to be tolerated. 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. |
| Color Diagnostics, |
RCV001183723 | SCV001349533 | uncertain significance | Cardiomyopathy | 2023-02-28 | criteria provided, single submitter | clinical testing | This missense variant replaces isoleucine with threonine at codon 630 of the PKP2 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 dilated cardiomyopathy (PMID: 24503780, 27532257). This variant has been identified in 3/251296 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. |
| Mayo Clinic Laboratories, |
RCV002260971 | SCV002541522 | uncertain significance | not provided | 2021-11-17 | criteria provided, single submitter | clinical testing |