Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Baylor Genetics | RCV001004217 | SCV001163078 | likely pathogenic | Autosomal recessive polycystic kidney disease | criteria provided, single submitter | clinical testing | ||
| Invitae | RCV001004217 | SCV001217360 | likely pathogenic | Autosomal recessive polycystic kidney disease | 2024-01-04 | criteria provided, single submitter | clinical testing | This sequence change affects codon 223 of the PKHD1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the PKHD1 protein. This variant also falls at the last nucleotide of exon 9, which is part of the consensus splice site for this exon. This variant is present in population databases (rs749454235, gnomAD 0.003%). This variant has been observed in individual(s) with autosomal recessive polycystic kidney disease (PMID: 12506140; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 813394). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001732010 | SCV001983699 | uncertain significance | not specified | 2021-09-17 | criteria provided, single submitter | clinical testing | Variant summary: PKHD1 c.667G>A (p.Gly223Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant also alters the last conserved nucleotide of exon 9 adjacent to the intron 9 splice donor site. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 2e-05 in 250824 control chromosomes. c.667G>A has been reported in the literature in multiple individuals from a consanguineous multiplex Pakistani family affected with Polycystic Kidney And Hepatic Disease (example, Bergmann_2003) and in at-least one Italian individual with this condition in whom a second variant was not identified following comprehensive genotyping for the PKHD1 gene (example, Melchionda_2016). These data indicate that the variant is likely to be associated with disease. However, the authors of the primary report do speculate that a non-causative outcome for this variant cannot be entirely ruled out (Bergmann_2003). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance citing an overlapping evidence utilized in the context of this analysis. Based on the evidence outlined above, until additional clinical segregation and/or functional evidence is identified, the variant was classified as VUS-possibly pathogenic. |
| Gene |
RCV002290520 | SCV002578658 | uncertain significance | not provided | 2023-01-19 | criteria provided, single submitter | clinical testing | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis is inconclusive as to whether the variant alters gene splicing; in the absence of RNA/functional studies the actual effect of this sequence change is unknown; This variant is associated with the following publications: (PMID: 25525159, 14741187, 27225849, 12506140) |
| Baylor Genetics | RCV003461308 | SCV004204562 | likely pathogenic | Polycystic kidney disease 4 | 2023-08-30 | criteria provided, single submitter | clinical testing |