Submissions for variant NM_138694.4(PKHD1):c.6121G>A (p.Gly2041Ser)

gnomAD frequency: 0.00020  dbSNP: rs199589074

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000664523	SCV000788499	uncertain significance	Autosomal recessive polycystic kidney disease	2017-01-25	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000732146	SCV000860056	uncertain significance	not provided	2018-03-02	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001526742	SCV001737212	uncertain significance	Polycystic kidney disease 4	2021-05-18	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001584528	SCV001821234	uncertain significance	not specified	2021-08-12	criteria provided, single submitter	clinical testing	Variant summary: PKHD1 c.6121G>A (p.Gly2041Ser) results in a non-conservative amino acid change located in the G8 domain of the encoded protein sequence which affects the last nucleotide of exon 37. Five 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: Four predict the variant weakens a 5' donor site. Four predict the variant creates a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 7.6e-05 in 251302 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in PKHD1 causing Polycystic Kidney And Hepatic Disease (7.6e-05 vs 0.0071), allowing no conclusion about variant significance. c.6121G>A has been reported in the literature in individuals affected with Polycystic Kidney And Hepatic Disease, without strong evidence for causality (Melchionda_2016, Burgamaier_2021). These reports do not provide unequivocal conclusions about association of the variant with Polycystic Kidney And Hepatic Disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx	RCV000732146	SCV002770038	uncertain significance	not provided	2023-03-28	criteria provided, single submitter	clinical testing	Reported without a second variant in a patient with polycystic kidney disease (Melchionda et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 33940108, 27225849, 32256442)
Invitae	RCV000664523	SCV003248888	uncertain significance	Autosomal recessive polycystic kidney disease	2021-09-10	criteria provided, single submitter	clinical testing	This sequence change replaces glycine with serine at codon 2041 of the PKHD1 protein (p.Gly2041Ser). The glycine residue is moderately conserved and there is a small physicochemical difference between glycine and serine. This variant also falls at the last nucleotide of exon 37, which is part of the consensus splice site for this exon. This variant is present in population databases (rs199589074, ExAC 0.09%). This missense change has been observed in individual(s) with polycystic kidney disease (PMID: 27225849). ClinVar contains an entry for this variant (Variation ID: 549940). 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"). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Natera, Inc.	RCV000664523	SCV002078059	uncertain significance	Autosomal recessive polycystic kidney disease	2018-07-03	no assertion criteria provided	clinical testing