Submissions for variant NM_138694.4(PKHD1):c.9241A>G (p.Ile3081Val)

gnomAD frequency: 0.00013  dbSNP: rs142146981

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000594992	SCV000707652	uncertain significance	not provided	2018-03-29	criteria provided, single submitter	clinical testing
Counsyl	RCV000671717	SCV000796723	uncertain significance	Autosomal recessive polycystic kidney disease	2017-12-28	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV001653942	SCV000897289	uncertain significance	Polycystic kidney disease 4	2022-04-05	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000671717	SCV001319933	uncertain significance	Autosomal recessive polycystic kidney disease	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Invitae	RCV000671717	SCV001421666	uncertain significance	Autosomal recessive polycystic kidney disease	2022-07-19	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 3081 of the PKHD1 protein (p.Ile3081Val). This variant is present in population databases (rs142146981, gnomAD 0.04%). This missense change has been observed in individual(s) with autosomal recessive polycystic kidney disease (PMID: 12506140). ClinVar contains an entry for this variant (Variation ID: 501331). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PKHD1 protein function. 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.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV001653942	SCV001870376	uncertain significance	Polycystic kidney disease 4	2021-07-29	criteria provided, single submitter	research	ACMG codes:PM2, PM3, PP3
GeneDx	RCV000594992	SCV001985427	uncertain significance	not provided	2019-10-11	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26489027, 14741187, 12506140)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002282260	SCV002571028	uncertain significance	not specified	2022-07-13	criteria provided, single submitter	clinical testing	Variant summary: PKHD1 c.9241A>G (p.Ile3081Val) results in a conservative amino acid change located in the Right handed beta helix domain (IPR039448) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 251108 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in PKHD1 causing Polycystic Kidney And Hepatic Disease (0.00014 vs 0.0071), allowing no conclusion about variant significance. c.9241A>G has been reported in the literature in individuals affected with Polycystic Kidney And Hepatic Disease (Bergmann_2003, Nicolaou_2016). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Mayo Clinic Laboratories, Mayo Clinic	RCV000594992	SCV004227246	uncertain significance	not provided	2023-03-06	criteria provided, single submitter	clinical testing	PM2
Natera, Inc.	RCV000671717	SCV002077957	uncertain significance	Autosomal recessive polycystic kidney disease	2018-06-15	no assertion criteria provided	clinical testing