Submissions for variant NM_138694.4(PKHD1):c.9998G>C (p.Arg3333Thr)

dbSNP: rs1057524563

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781721	SCV000919989	likely pathogenic	Autosomal recessive polycystic kidney disease	2020-07-31	criteria provided, single submitter	clinical testing	Variant summary: PKHD1 c.9998G>C (p.Arg3333Thr) results in a non-conservative amino acid change in the encoded protein sequence. The variant involves the alteration of the last nucleotide of exon 59 at an exon/intron boundary. Three of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 250686 control chromosomes (gnomAD and publication). c.9998G>C has been reported in the literature in the compound heterozygous state in an affected individual with fetal presentation of Polycystic Kidney And Hepatic Disease (Sharp_2005). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submitter (evaluation after 2014) cites the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae	RCV000781721	SCV000954451	pathogenic	Autosomal recessive polycystic kidney disease	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with threonine, which is neutral and polar, at codon 3333 of the PKHD1 protein (p.Arg3333Thr). This variant also falls at the last nucleotide of exon 59, which is part of the consensus splice site for this exon. This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individual(s) with clinical features of polycystic kidney disease and/or PKHD1-related conditions (PMID: 15805161; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 633353). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV002469287	SCV002765609	likely pathogenic	not provided	2022-06-13	criteria provided, single submitter	clinical testing	Alters the last nucleotide of the exon and is predicted to destroy the splice donor site and result in aberrant splicing; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported with a second variant (phase unknown) in a patient with autosomal recessive polycystic kidney disease in published literature (Sharp et al., 2005); This variant is associated with the following publications: (PMID: 15805161)
Baylor Genetics	RCV003461059	SCV004204812	likely pathogenic	Polycystic kidney disease 4	2022-01-10	criteria provided, single submitter	clinical testing