Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000170946 | SCV000223506 | uncertain significance | not provided | 2018-11-19 | criteria provided, single submitter | clinical testing | The P174S variant of uncertain significance in the HCN4 gene has been reported in one individual with sick sinus syndrome (Jou et al., 2017); however, additional clinical details and segregation information were not provided. This variant is observed in 16/158162 (0.01%) alleles from individuals of multiple ethnic backgrounds in large population cohorts (Lek et al., 2016). The P174S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Finally, while functional assays using zebrafish embryos suggest that this variant is disease-causing (Jou et al., 2017), additional studies are needed to confirm this finding. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign. |
| Invitae | RCV000467858 | SCV000541565 | uncertain significance | Brugada syndrome 8 | 2020-09-30 | criteria provided, single submitter | clinical testing | This sequence change replaces proline with serine at codon 174 of the HCN4 protein (p.Pro174Ser). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and serine. This variant is present in population databases (rs542532555, ExAC 0.05%) but has not been reported in the literature in individuals with a HCN4-related disease. ClinVar contains an entry for this variant (Variation ID: 190787). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: (SIFT: Tolerated; PolyPhen-2: Benign; Align-GVGD: Class C0). The serine amino acid residue is also found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. |
| Center for Human Genetics, |
RCV000497368 | SCV000579561 | uncertain significance | Hypertrophic cardiomyopathy | 2017-04-30 | criteria provided, single submitter | clinical testing |