ClinVar Miner

Submissions for variant NM_138694.4(PKHD1):c.5060T>C (p.Ile1687Thr) (rs794727566)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000177676 SCV000332132 pathogenic not provided 2015-07-21 criteria provided, single submitter clinical testing
GeneDx RCV000177676 SCV000565375 likely pathogenic not provided 2017-03-21 criteria provided, single submitter clinical testing The I1687T variant in the PKHD1 gene has been reported previously in association with autosomal recessive polycystic kidney disease (Bergmann et al., 2005). The I1687T variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The I1687T 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 where amino acids with similar properties to Isoleucine are tolerated across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. The I1687T variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded.
Invitae RCV000394147 SCV000629922 likely pathogenic Autosomal recessive polycystic kidney disease 2017-11-21 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 1687 of the PKHD1 protein (p.Ile1687Thr). The isoleucine residue is moderately conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with polycystic kidney disease (PMID: 15698423, 15706593, Invitae). ClinVar contains an entry for this variant (Variation ID: 196807). 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: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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