Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000489232 | SCV000577203 | uncertain significance | not provided | 2017-04-07 | criteria provided, single submitter | clinical testing | A variant of uncertain significance has been identified in the PNPLA6 gene. The R1314H variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R1314H 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 R1314H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is not conserved and in silico analysis predicts this variant likely does not alter the protein structure/function. However, a different missense substitution at the same position (R1314G) and a missense variant at a nearby residue (R1311W) have been reported in association with Gordon Holmes syndrome (Synofzik et al., 2014; Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. |
| Labcorp Genetics |
RCV001056938 | SCV001221405 | uncertain significance | Hereditary spastic paraplegia 39 | 2022-07-12 | 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: "Benign"; Align-GVGD: "Class C0". The histidine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 426688). This variant has not been reported in the literature in individuals affected with PNPLA6-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1314 of the PNPLA6 protein (p.Arg1314His). |