Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Counsyl | RCV000666503 | SCV000790808 | uncertain significance | Autosomal recessive polycystic kidney disease | 2017-04-10 | criteria provided, single submitter | clinical testing | |
| Baylor Genetics | RCV000666503 | SCV001163068 | likely pathogenic | Autosomal recessive polycystic kidney disease | criteria provided, single submitter | clinical testing | ||
| Invitae | RCV000666503 | SCV002965247 | likely pathogenic | Autosomal recessive polycystic kidney disease | 2023-08-20 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 466 of the PKHD1 protein (p.Gly466Ala). This variant is present in population databases (rs750730042, gnomAD 0.006%). This missense change has been observed in individual(s) with polycystic kidney disease (PMID: 15698423). ClinVar contains an entry for this variant (Variation ID: 551441). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PKHD1 protein function. This variant disrupts the p.Gly466 amino acid residue in PKHD1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20413436, 27225849, 27752906). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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, |
RCV000666503 | SCV004039103 | likely pathogenic | Autosomal recessive polycystic kidney disease | 2023-08-11 | criteria provided, single submitter | clinical testing | Variant summary: PKHD1 c.1397G>C (p.Gly466Ala) results in a non-conservative amino acid change located in the PA14/GLEYA domain (IPR037524) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251256 control chromosomes (gnomAD). c.1397G>C has been reported in the literature in heterozygous state (i.e. without identifying a variant in trans) in 3 patients, from two families, where one of them was affected with predominant liver phenotype (Bergmann_2005). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. However, other missense changes affecting the same residue (G466E/R) have been reported in affected individuals (HGMD), and one of them (G466E) is classified as pathogenic by multiple reputable laboratories in ClinVar. The following publication has been ascertained in the context of this evaluation (PMID: 15698423). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. One submitter classified the variant as likely pathogenic, and one submitter classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic. |
| Baylor Genetics | RCV003459579 | SCV004204556 | likely pathogenic | Polycystic kidney disease 4 | 2023-09-03 | criteria provided, single submitter | clinical testing |