Total submissions: 6
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Counsyl | RCV000500109 | SCV000795268 | likely pathogenic | Autosomal recessive polycystic kidney disease | 2017-11-07 | criteria provided, single submitter | clinical testing | |
| Fulgent Genetics, |
RCV002506218 | SCV002807113 | likely pathogenic | Polycystic kidney disease 4 | 2021-10-22 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV000500109 | SCV003469363 | pathogenic | Autosomal recessive polycystic kidney disease | 2022-04-08 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 434018). This missense change has been observed in individual(s) with polycystic kidney disease (PMID: 12846734, 12874454). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 1942 of the PKHD1 protein (p.Asp1942Gly). |
| Revvity Omics, |
RCV002506218 | SCV003808437 | uncertain significance | Polycystic kidney disease 4 | 2021-06-16 | criteria provided, single submitter | clinical testing | |
| Baylor Genetics | RCV002506218 | SCV004204821 | pathogenic | Polycystic kidney disease 4 | 2021-11-16 | criteria provided, single submitter | clinical testing | |
| Department of Pathology and Laboratory Medicine, |
RCV001291854 | SCV000592897 | pathogenic | Polycystic kidney disease | no assertion criteria provided | clinical testing | The PKHD1 p.Asp1942Gly variant was identified in 3 of 560 proband chromosomes (one homozygous individual) (frequency: 0.013) from unrelated Spanish, American and British individuals or families with ARPKD and was not identified in 620 control chromosomes from healthy individuals (Furu 2004, Sharp 2005, Rosetti 2003, Adeva 2006). Furu et al (2004) identified the mutation in an American caucasian individual in which severe perinatal disease led to neonatal death; with the variant co-occurring with another PKHD1 pathogenic mutation (c.1159_1161delAAT, p.Asn387del). Adeva et al (2006) identified the variant in both of the unrelated parents of an affected child who with neonatal demise. A novel protein domain, G8, was identified, that contains 8 conserved glycine residues in which missense variants (p.Asp1942Gly included) reported to be associated with ARPKD disease are localized in (He 2004). The variant was identified in RWTH AAachen University ARPKD database (classification pathogenic) and PKHD1-LOVD (unclassified); and was not identified in dbSNP, Clinvitae database, the ClinVar database, GeneInsight COGR database, 1000 Genomes Project, NHLBI GO Exome Sequencing Project, and the Exome Aggregation Consortium database (March 14, 2016). The p.Asp1942 residue is not conserved across mammals, however 4 of 5 computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. |