Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Victorian Clinical Genetics Services, |
RCV002470887 | SCV002769167 | uncertain significance | Polycystic kidney disease 4 | 2019-08-28 | criteria provided, single submitter | clinical testing | A heterozygous missense variant was identified NM_138694.3(PKHD1):c.2948G>A in exon 27 of 67 of the PKHD1 gene. This substitution is predicted to create a major amino acid change from cysteine to tyrosine at position 983 of the protein, NP_619639.3(PKHD1):p.(Cys983Tyr). The cysteine at this position has very high conservation (100 vertebrates, UCSC), and is located within the IPT/TIG 4 functional domain. In silico software predicts this variant to be disease causing (Polyphen, SIFT, CADD, Mutation Taster). The variant is not present in the gnomAD population database. The variant has been previously reported as a VUS in a clinical testing setting (ClinVar). Subsequent analysis of parental samples indicated this variant was paternally inherited. Based on information available at the time of curation, this variant has been classified as a VARIANT of UNCERTAIN SIGNIFICANCE (VUS) with POTENTIAL CLINICAL RELEVANCE. |
| Department of Pathology and Laboratory Medicine, |
RCV000503903 | SCV000592890 | uncertain significance | Polycystic kidney disease | no assertion criteria provided | clinical testing | The PKHD1 p.Cys983Tyr variant was not identified in the literature, nor was it identified in the dbSNP, NHLBI Exome Sequencing Project, Exome Aggregation Consortium (14 March 2016), Clinvitae, the ClinVar, GeneInsight COGR, MutDB, RWTH AAachen University ARPKD and PKHD1-LOVD databases. The p.Cys983 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the Tyrosine variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. |