ClinVar Miner

Submissions for variant NM_138694.4(PKHD1):c.9877G>A (p.Asp3293Asn) (rs1060501356)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000476666 SCV000545851 likely pathogenic Autosomal recessive polycystic kidney disease 2017-02-26 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 3293 of the PKHD1 protein (p.Asp3293Asn). The aspartic acid residue is moderately conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a PKHD1-related disease. This variant, in combination with a pathogenic PKHD1 missense on the opposite chromosome (in trans), has been found to segregate with PKHD1-related disease in two affected siblings (Invitae). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). A different missense substitution at this codon (p.Asp3293Val) has been determined to be pathogenic (PMID: 12506140, 128744540, 15698423). This suggests that the aspartic acid residue is critical for PKHD1 protein function and that other missense substitutions at this position may also be pathogenic, although this has not been confirmed by experimental studies. In summary, this variant is a rare missense change with uncertain impact on protein function. It is absent from the general population and segregates with PKHD1-related disease in a single family. This evidence indicates that the variant is pathogenic, but additional data is needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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