ClinVar Miner

Submissions for variant NM_138694.4(PKHD1):c.2507T>C (p.Val836Ala) (rs199568593)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000779513 SCV000916157 likely pathogenic Autosomal recessive polycystic kidney disease 2018-12-05 criteria provided, single submitter clinical testing The PKHD1 c.2507T>C (p.Val836Ala) is a missense variant that has been reported in at least four studies in a compound heterozygous state in five individuals with autosomal recessive polycystic kidney disease (ARPKD) (Hao et al 2014; Liu et al. 2014; Kang et al. 2016; Cho et al. 2017). Hao et al. (2014) performed whole exome sequencing on 10 year-old male dizygotic twins with Caroli syndrome and identified the p.Val836Ala variant in a compound heterozygous state in both twins. Twin A had a more severe clinical presentation including liver cirrhosis, hypersplenism, and polycystic kidneys noted by age seven. Twin B had intrahepatic bile duct dilation, but otherwise no overt clinical symptoms. Liu et al. (2014) performed sequence analysis of the PKHD1 gene in three Chinese children with ARPKD. A seven year old boy with polycystic kidneys, bilateral enlargement of the kidneys, loss of corticomedullary differentiation, hepatosplenomegaly and portal hypertension, was found to be compound heterozygous for the p.Val836Ala variant with another missense variant. The p.Val836Ala variant was absent from 322 controls and is reported at a frequency of 0.001273 in the East Asian population of the Exome Aggregation Consortium. Based on the evidence, the p.Val836Ala variant is classified as likely pathogenic for the autosomal recessive form of polycystic kidney disease. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Blueprint Genetics RCV000788709 SCV000927915 pathogenic not provided 2018-09-05 criteria provided, single submitter clinical testing
Invitae RCV000779513 SCV000950961 likely pathogenic Autosomal recessive polycystic kidney disease 2018-11-20 criteria provided, single submitter clinical testing This sequence change replaces valine with alanine at codon 836 of the PKHD1 protein (p.Val836Ala). The valine residue is moderately conserved and there is a small physicochemical difference between valine and alanine. This variant is present in population databases (rs199568593, ExAC 0.1%). This variant has been observed on the opposite chromosome (in trans) from other pathogenic variants in an individuals affected with autosomal recessive cystic kidney disease (PMID: 24710345, 25124979). This variant has also been observed in combination with other rare variants in PKHD1 in several individuals affected with autosomal recessive cystic kidney disease (PMID: 29643536, 27491411). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.

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