Submissions for variant NM_138694.4(PKHD1):c.10036T>C (p.Cys3346Arg) (rs149798764)

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics	RCV000587211	SCV000231850	uncertain significance	not provided	2018-06-11	criteria provided, single submitter	clinical testing
Invitae	RCV000195797	SCV000255207	uncertain significance	Autosomal recessive polycystic kidney disease	2015-02-25	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine with arginine at codon 3346 of the PKHD1 protein (p.Cys3346Arg). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and arginine. This variant has been reported in the literature and is present in population databases (rs149798764, 0.07%). This variant has been reported in an individual with autosomal recessive polycystic kidney disease. It has also been reported to co-occur with a homozygous variant an additional gene in an individual with Meckel-Gruber syndrome. (PMID: 12846734, 21493627). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this is a rare missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.
Integrated Genetics/Laboratory Corporation of America	RCV000587211	SCV000699840	uncertain significance	not provided	2017-05-08	criteria provided, single submitter	clinical testing	Variant summary: The PKHD1 c.10036T>C (p.Cys3346Arg) variant causes a missense change involving the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 41/121406 control chromosomes at a frequency of 0.0003377, which does not exceed the estimated maximal expected allele frequency of a pathogenic PKHD1 variant (0.0070711). This variant was reported in ARPKD patients in compound heterozygosity with other presumably pathogenic/likely pathogenic variants in multiple studies (ROSSETTI_Kidney Int_2003, Tavira_gene_2015, and Eisenberger_PlosONE_2014). One study reported this variant to co-occur with a homozygous variant an additional gene in an individual with Meckel-Gruber syndrome. (Hopp_2011), however, the zygosity of this variant was not mentioned therefore, the possibility of incidental heterozysity for this variant cannot be ruled out and this evidence has not been weighted in this classification.in Multiple clinical diagnostic laboratories via ClinVar have classified this variant as uncertain significance without evidence for independent evaluation. However, a locus specific database (http://www.humgen.rwth-aachen.de) reports this variant as "Pathogenic". Taken together, this variant is classified as VUS-possibly pathogenic, until more clinical and functional data becomes available.
Counsyl	RCV000195797	SCV000793823	uncertain significance	Autosomal recessive polycystic kidney disease	2017-11-14	criteria provided, single submitter	clinical testing
SIB Swiss Institute of Bioinformatics	RCV000195797	SCV000803504	uncertain significance	Autosomal recessive polycystic kidney disease	2018-05-31	criteria provided, single submitter	curation	This variant is interpreted as a Uncertain Significance - Conflicting Evidence, for Polycystic kidney disease 4 with or without polycystic liver disease, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PM3 => For recessive disorders, detected in trans with a pathogenic variant (PMID:12846734). BS2 => Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.
Department of Genetics,Sultan Qaboos University Hospital, Oman	RCV000195797	SCV000891698	pathogenic	Autosomal recessive polycystic kidney disease	2017-12-30	criteria provided, single submitter	clinical testing
Fulgent Genetics,Fulgent Genetics	RCV000195797	SCV000897288	uncertain significance	Autosomal recessive polycystic kidney disease	2018-10-31	criteria provided, single submitter	clinical testing
Illumina Clinical Services Laboratory,Illumina	RCV000195797	SCV000915169	uncertain significance	Autosomal recessive polycystic kidney disease	2018-12-21	criteria provided, single submitter	clinical testing	The PKHD1 c.10036T>C (p.Cys3346Arg) variant is a missense variant that has been reported in a compound heterozygous state in two unrelated individuals with polycystic kidney disease (Rosetti et al. 2003; Tatvira et al. 2015). It has also been reported in a heterozygous state in two individuals with polycystic kidney in whom an alternative molecular diagnosis was identified (Hopp et al. 2011; Eisenberger et al. 2015). The p.Cys3346Arg variant was absent from 50 control individuals but is reported at a frequency of 0.001061 in the Ashkenazi Jewish population of the Genome Aggregation Database. Notably, the variant is reported in a homozygous state in one individual in this population. However, disease severity is variable, and rare cases of adult onset have been reported. Functional studies of this variant have not been conducted. Based on the available evidence, the p.Cys3346Arg variant is classified as of uncertain significance but suspicious for pathogenicity for polycystic kidney disease. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Medical Genetics Department, and Science and Technology Unit,Umm-al-Qura University	RCV001263488	SCV001422490	pathogenic	Malignant tumor of colon	2018-10-06	no assertion criteria provided	curation	It is well established that the PKHD1 mutations are associated with autosomal recessive polycystic kidney disease (ARPKD). It has been shown that the silencing of the PKHD1 gene promotes cell migration and invasion; and in the category of cell adhesion and motility genes PKHD1 has the highest frequency of mutations. Although, PKHD1 mutations are also detected in certain cancer types, to our knowledge in rare tumors such as, amelanotic ano-rectal melanoma (AMM), are not reported. The anorectal- amelanotic melanoma (AMM) represents about 2% - 8% of all melanomas, almost 30% of anorectal melanomas are amelanotic, and they are distinct because they contain a little or no-pigmentation. In order to determine the PKHD1 gene mutation patterns in this tumor we have analyzed the tumor DNA by Ion Proton Next generation DNA sequencing. The present case is from an 84 years old female Saudi patient diagnosed with AMM. This AMM had metastasized to the left-lung in the patient indicating its malignant nature. Next-generation DNA sequencing identified a pathogenic missense mutation (rs149798764) in this tumor, in g.348121T>C, NG_008753.1: on chromosome 6 it changes coding Cys3346Arg in PKHD1 gene. There are 8 submission presents for this variant with variant ID 198306 in ClinVar data base for this mutation. But for the AMM tumors this is the novel finding.
Natera, Inc.	RCV000195797	SCV001453262	uncertain significance	Autosomal recessive polycystic kidney disease	2017-05-07	no assertion criteria provided	clinical testing