ClinVar Miner

Submissions for variant NM_004722.4(AP4M1):c.496C>T (p.Pro166Ser)

gnomAD frequency: 0.00004  dbSNP: rs201290190
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000425372 SCV000530945 uncertain significance not provided 2016-08-16 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the AP4M1 gene. The P166S variant has notbeen published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge.It was not observed in approximately 6,500 individuals of European and African American ancestry inthe NHLBI Exome Sequencing Project, indicating it is not a common benign variant in thesepopulations. The P166S variant is a non-conservative amino acid substitution, which is likely toimpact secondary protein structure as these residues differ in polarity, charge, size and/or otherproperties. This substitution occurs at a position that is conserved across species and in silico analysispredicts this variant is probably damaging to the protein structure/function. However, missensevariants in nearby residues have not been reported in the Human Gene Mutation Database inassociation with spastic paraplegia (Stenson et al., 2014). Therefore, based on the currently availableinformation, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Labcorp Genetics (formerly Invitae), Labcorp RCV001325937 SCV001516947 uncertain significance Hereditary spastic paraplegia 50 2022-08-13 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 166 of the AP4M1 protein (p.Pro166Ser). This variant is present in population databases (rs201290190, gnomAD 0.009%). This variant has not been reported in the literature in individuals affected with AP4M1-related conditions. ClinVar contains an entry for this variant (Variation ID: 388602). 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. 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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