ClinVar Miner

Submissions for variant NM_020956.2(PRX):c.*1751C>T (rs144305922)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000236385 SCV000293815 uncertain significance not provided 2016-01-21 criteria provided, single submitter clinical testing The R516W variant has not been published as a pathogenic variant, nor has it been reported as a benign variant 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 R516W 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. However, this substitution occurs at a position that is not conserved. 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.
Fulgent Genetics,Fulgent Genetics RCV000764202 SCV000895205 uncertain significance Dejerine-Sottas disease; Charcot-Marie-Tooth disease, demyelinating, type 4F 2018-10-31 criteria provided, single submitter clinical testing
Invitae RCV000802296 SCV000942121 uncertain significance Charcot-Marie-Tooth disease type 4 2019-10-23 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 516 of the PRX protein (p.Arg516Trp). The arginine residue is weakly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs144305922, ExAC 0.05%). This variant has not been reported in the literature in individuals with PRX-related disease. ClinVar contains an entry for this variant (Variation ID: 246316). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.
Illumina Clinical Services Laboratory,Illumina RCV001136189 SCV001296011 uncertain significance Charcot-Marie-Tooth disease, demyelinating, type 4F 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

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