ClinVar Miner

Submissions for variant NM_181882.3(PRX):c.553C>T (p.Arg185Cys)

gnomAD frequency: 0.00008  dbSNP: rs376863946
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001050695 SCV001214815 uncertain significance Charcot-Marie-Tooth disease type 4 2023-10-13 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 185 of the PRX protein (p.Arg185Cys). This variant is present in population databases (rs376863946, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with PRX-related conditions. ClinVar contains an entry for this variant (Variation ID: 847198). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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.
Ambry Genetics RCV002348394 SCV002653776 uncertain significance Inborn genetic diseases 2019-09-26 criteria provided, single submitter clinical testing The p.R185C variant (also known as c.553C>T), located in coding exon 4 of the PRX gene, results from a C to T substitution at nucleotide position 553. The arginine at codon 185 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV002471018 SCV002768528 uncertain significance Charcot-Marie-Tooth disease type 4F 2019-08-28 criteria provided, single submitter clinical testing A heterozygous missense variant was identified, NM_181882.2(PRX):c.553C>T in exon 7 of 7 of the PRX gene. This substitution is predicted to create a major amino acid change from arginine to cysteine at position 185 of the protein, NP_870998.2(PRX):p.(Arg185Cys). The arginine at this position has low conservation (100 vertebrates, UCSC), but is located within the nuclear localisation signal motif. In silico software predictions of the pathogenicity of this variant are conflicting (PolyPhen, SIFT, CADD, MutationTaster). The variant is present in the gnomAD population database at a frequency of 0.0028% (6 heterozygotes; 0 homozygotes). An alternative change to histidine at the same residue has also been reported in the gnomAD database at a frequency of 0.097%. The variant has not previously been reported in clinical cases. Based on information available at the time of curation, this variant has been classified as a VARIANT of UNCERTAIN SIGNIFICANCE (VUS) with LOW CLINICAL RELEVANCE.

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