ClinVar Miner

Submissions for variant NM_138694.4(PKHD1):c.9998G>C (p.Arg3333Thr) (rs1057524563)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000781721 SCV000919989 likely pathogenic Autosomal recessive polycystic kidney disease 2017-11-09 criteria provided, single submitter clinical testing Variant summary: The PKHD1 c.9998G>C (p.Arg3333Thr) variant involves the alteration of a conserved nucleotide that is the last nucleotide of the exon 59 at an exon/intron boundary. 3/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not accessible at the time of evaluation). 4/5 splice prediction tools predict a significant impact to normal splicing and ESE finder predicts that this variant may affect multiple ESE sites at the locus. However, these predictions have yet to be confirmed by functional studies. This variant was found in 1/245538 control chromosomes at a frequency of 0.0000041, which does not exceed the estimated maximal expected allele frequency of a pathogenic PKHD1 variant (0.0070711). The variant was found in an affected individual with fetal presentation who was compound heterozygous for the variant and another splice variant (c.5237-1G>A; Sharp_2005). Taken together, this variant is classified as likely pathogenic.
Invitae RCV000781721 SCV000954451 likely pathogenic Autosomal recessive polycystic kidney disease 2018-08-23 criteria provided, single submitter clinical testing This sequence change replaces arginine with threonine at codon 3333 of the PKHD1 protein (p.Arg3333Thr). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and threonine. This variant also falls at the last nucleotide of exon 59 of the PKHD1 coding sequence, which is part of the consensus splice site for this exon. This variant is not present in population databases (ExAC no frequency). This variant has been observed on the opposite chromosome (in trans) from another likely pathogenic variant in an individual affected with polycystic kidney disease (PMID: 15805161). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. 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: "Possibly Damaging"; Align-GVGD: "Class C0"). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. 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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