ClinVar Miner

Submissions for variant NM_025219.3(DNAJC5):c.524C>T (p.Pro175Leu) (rs761982169)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000498553 SCV000589324 uncertain significance not provided 2017-06-01 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the DNAJC5 gene. The P175L variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The P175L variant is observed in 3/15352 (0.02%) alleles from individuals of European background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The P175L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, missense variants in nearby residues have not been reported in Human Gene Mutation Database in association with DNAJC5-related disorders (Stenson et al., 2014). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV001049122 SCV001213156 uncertain significance Neuronal ceroid lipofuscinosis 2019-03-06 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 175 of the DNAJC5 protein (p.Pro175Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs761982169, ExAC 0.02%). This variant has not been reported in the literature in individuals with DNAJC5-related conditions. ClinVar contains an entry for this variant (Variation ID: 431814). 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: "Deleterious"; 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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