ClinVar Miner

Submissions for variant NM_181882.2(PRX):c.3769G>A (p.Gly1257Arg) (rs200332462)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Fulgent Genetics,Fulgent Genetics RCV000764201 SCV000895204 uncertain significance Dejerine-Sottas disease; Charcot-Marie-Tooth disease, demyelinating, type 4F 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000236523 SCV000292971 uncertain significance not provided 2015-07-17 criteria provided, single submitter clinical testing The G1257R variant has not been published as pathogenic, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, but the 1000 Genomes Project reports G1257R was observed in 2/1006 (0.2%) alleles from individuals of European background. The G1257R 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, and Arginine is observed in this position in evolution. In silico analysis predicts the G1257R variant likely does not alter 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
Invitae RCV000819134 SCV000959777 uncertain significance Charcot-Marie-Tooth disease type 4 2018-12-20 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 1257 of the PRX protein (p.Gly1257Arg). The glycine residue is moderately conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs200332462, ExAC 0.03%). This variant has not been reported in the literature in individuals with PRX-related disease. ClinVar contains an entry for this variant (Variation ID: 245824). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0". The arginine 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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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