Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000483365 | SCV000572982 | uncertain significance | not provided | 2017-02-10 | criteria provided, single submitter | clinical testing | A variant of uncertain significance has been identified in the PNPLA6 gene. The A485T variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The A485T variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The A485T 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. This substitution occurs at a position that is conserved across species. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. |
| Labcorp Genetics |
RCV000646159 | SCV000767917 | uncertain significance | Hereditary spastic paraplegia 39 | 2020-11-12 | 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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0". The threonine amino acid residue is 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 and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with PNPLA6-related disease. ClinVar contains an entry for this variant (Variation ID: 423302). This variant is present in population databases (rs763642095, ExAC 0.01%). This sequence change replaces alanine with threonine at codon 485 of the PNPLA6 protein (p.Ala485Thr). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and threonine. |