Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Victorian Clinical Genetics Services, |
RCV002470609 | SCV002768827 | likely pathogenic | Polycystic kidney disease 4 | 2022-06-24 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with polycystic kidney disease 4, with or without hepatic disease (MIM#263200). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity (GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from aspartic acid to tyrosine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2; 1 heterozygote, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0803 - This variant has limited previous evidence of pathogenicity in an unrelated individual. It has been reported in a patient with autosomal recessive polycystic kidney disease as compound heterozygous with an NMD-predicted variant (Yan, Y. et al. (2016)). (SP) 1007 - No published functional evidence has been identified for this variant. (I) 1102 - Strong phenotype match for this individual. (SP) 1201 - Heterozygous variant detected in trans with a second pathogenic heterozygous variant (NM_138694.3(PKHD1):c.9825delT; p.(Gln3276Lysfs*9)) in a recessive disease. (SP) 1206 - This variant has been shown to be paternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |
| Baylor Genetics | RCV002470609 | SCV004204582 | likely pathogenic | Polycystic kidney disease 4 | 2023-08-16 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003479430 | SCV004223692 | uncertain significance | not specified | 2023-11-10 | criteria provided, single submitter | clinical testing | Variant summary: PKHD1 c.10315G>T (p.Asp3439Tyr) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250950 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.10315G>T has been reported in the literature in at least one compound heterozygous individual affected with Polycystic Kidney And Hepatic Disease (Qiu_2020). The variant has also been identified in another compound heterozygous individual with congenital anomalies of the kidney and urinary tract (CAKUT). This patient's phenotype included hepatomegaly and bilateral renal hypodysplasia, which is not the expected kidney phenotype seen in Polycystic Kidney and Hepatic Disease (Liu_2022). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 36549658, 33123899). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as uncertain significance. |