ClinVar Miner

Submissions for variant NM_181882.2(PRX):c.4219T>G (p.Ser1407Ala) (rs146468976)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000236345 SCV000293334 uncertain significance not specified 2015-11-12 criteria provided, single submitter clinical testing The S1407A 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 S1407A 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. This substitution occurs at a position that is conserved across species. However, 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.
Invitae RCV000542374 SCV000658028 uncertain significance Charcot-Marie-Tooth disease type 4 2018-10-22 criteria provided, single submitter clinical testing This sequence change replaces serine with alanine at codon 1407 of the PRX protein (p.Ser1407Ala). The serine residue is moderately conserved and there is a moderate physicochemical difference between serine and alanine. This variant is present in population databases (rs146468976, ExAC 0.009%) but has not been reported in the literature in individuals with a PRX-related disease. ClinVar contains an entry for this variant (Variation ID: 246041). 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 tolerated, but these predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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