ClinVar Miner

Submissions for variant NM_138694.4(PKHD1):c.9719G>T (p.Arg3240Leu) (rs146649803)

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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 RCV000153706 SCV000203264 uncertain significance not provided 2014-03-11 criteria provided, single submitter clinical testing
Invitae RCV000200664 SCV000253724 likely pathogenic Autosomal recessive polycystic kidney disease 2019-09-27 criteria provided, single submitter clinical testing This sequence change replaces arginine with leucine at codon 3240 of the PKHD1 protein (p.Arg3240Leu). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and leucine. This variant has been reported in the literature and is present in population databases at a very low frequency (rs146649803, 0.001%). It was observed in trans with a likely pathogenic missense variant (p.Trp2736Gln) in a fetus affected with polycystic kidney disease (PMID: 15805161). ClinVar also contains an entry for this variant (RCV000153706). A different missense substitution at this codon (p.Arg3240Glu) is reported to be deleterious (PMID: 15698423). This indicates that the arginine residue is important for PKHD1 protein function. 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: "Probably Damaging"; Align-GVGD: "Class C0"). Experiments testing the impact of this missense change on protein function have not been reported. In summary, this is a rare missense substitution with uncertain impact on protein function. However, it has been observed in combination with a likely pathogenic missense variant in an affected fetus and it is predicted to affect a functionally important amino acid. For these reasons, this variant has been classified as Likely Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000780600 SCV000918008 uncertain significance not specified 2017-12-11 criteria provided, single submitter clinical testing Variant summary: The c.9719G>T (pArg3240Leu) in PKHD1 gene is a missense variant involves a conserved nucleotide located outside of any known functional domain or repeat. The 4/4 in silico tools used predict damaging outcome for this variant, however no functional studies supporting these predictions were published at the time of evaluation. The c.9719G>T was identified in the control population dataset of gnomAD at a low frequency of 0.000004 (1/245990 chrs tested). The observed frequencies do not exceed the maximum expected allele frequency for a pathogenic variant of 0.007, suggesting that it is not a common polymorphism. The variant has been reported in compound heterozygosity in 1 fetal sample with confirmed dx of ARPKD and is cited as VUS/Likely Pathogenic by reputable databases/clinical laboratories. In addition, other alterations of Arg3240 codon have been reported in association with ARPKD. Taken together, the variant was classified as VUS-Possibly Pathogenic, until new information becomes available.

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