ClinVar Miner

Submissions for variant NM_014855.3(AP5Z1):c.2352C>A (p.Asn784Lys)

gnomAD frequency: 0.00002  dbSNP: rs748913228
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV001756826 SCV001995050 uncertain significance not provided 2019-10-25 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV002471147 SCV002768652 uncertain significance Hereditary spastic paraplegia 48 2019-08-28 criteria provided, single submitter clinical testing A heterozygous missense variant, NM_014855.2(AP5Z1):c.2352C>A, has been identified in exon 17 of 17 of the AP5Z1 gene. The variant is predicted to result in a moderate amino acid change from asparagine to lysine at position 784 of the protein (NP_055670.1(AP5Z1):p.(Asn784Lys)). The asparagine residue at this position has low conservation (100 vertebrates, UCSC), but is not located within a well established functional domain. In silico predictions of pathogenicity for this variant are conflicting (Polyphen, SIFT, CADD, Mutation Taster). The variant is absent in population databases (gnomAD) and has not been previously reported in clinical cases. Based on the information available at the time of curation, this variant has been classified as a VARIANT of UNCERTAIN SIGNIFICANCE (VUS).
Invitae RCV002471147 SCV003486781 uncertain significance Hereditary spastic paraplegia 48 2022-07-30 criteria provided, single submitter clinical testing This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 784 of the AP5Z1 protein (p.Asn784Lys). This variant is present in population databases (rs748913228, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with AP5Z1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1309758). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably 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.

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