ClinVar Miner

Submissions for variant NM_181882.2(PRX):c.3656C>T (p.Pro1219Leu) (rs201393544)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000236735 SCV000292765 uncertain significance not provided 2015-04-14 criteria provided, single submitter clinical testing The P1219L variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The 1000 Genomes Project reports P1219L was observed in 1/198 (0.5%) alleles from individuals of European background in Utah. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. The P1219L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. Based on the currently available information, it is unclear whether the P1219L variant is a pathogenic mutation or a rare benign variant.
Invitae RCV000703799 SCV000832718 uncertain significance Charcot-Marie-Tooth disease type 4 2018-03-25 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 1219 of the PRX protein (p.Pro1219Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs201393544, ExAC 0.02%). This variant has not been reported in the literature in individuals with PRX-related disease. ClinVar contains an entry for this variant (Variation ID: 245707). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.

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