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

gnomAD frequency: 0.00024  dbSNP: rs149798764

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	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	2022-08-20	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 3346 of the PKHD1 protein (p.Cys3346Arg). This variant is present in population databases (rs149798764, gnomAD 0.1%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with autosomal recessive polycystic kidney disease (PMID: 12846734, 25701400). ClinVar contains an entry for this variant (Variation ID: 198306). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003993862	SCV000699840	uncertain significance	not specified	2024-02-20	criteria provided, single submitter	clinical testing	Variant summary: PKHD1 c.10036T>C (p.Cys3346Arg) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00033 in 251394 control chromosomes in the gnomAD database, including 1 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in PKHD1 causing Polycystic Kidney And Hepatic Disease (0.00033 vs 0.0071), allowing no conclusion about variant significance. c.10036T>C has been reported in the literature in individuals affected with Polycystic Kidney And Hepatic Disease (Rossetti_2003, Tabira_2015, Domingo-Gallego_2022). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 15805161, 25701400, 12846734, 14741187, 33532864). ClinVar contains an entry for this variant (Variation ID: 198306). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
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, Sultan Qaboos University	RCV001331691	SCV000891698	uncertain significance	Polycystic kidney disease 4	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 Laboratory Services, 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.
Baylor Genetics	RCV001331691	SCV001523787	uncertain significance	Polycystic kidney disease 4	2020-04-07	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Pars Genome Lab	RCV001331691	SCV001652849	uncertain significance	Polycystic kidney disease 4	2021-05-18	criteria provided, single submitter	clinical testing
Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital	RCV001331691	SCV001984625	uncertain significance	Polycystic kidney disease 4	2020-01-06	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001331691	SCV003808433	uncertain significance	Polycystic kidney disease 4	2023-05-02	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000587211	SCV004227245	uncertain significance	not provided	2022-11-21	criteria provided, single submitter	clinical testing	PP3, PM3
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV001331691	SCV004806625	uncertain significance	Polycystic kidney disease 4	2024-03-26	criteria provided, single submitter	clinical testing
Medical Genetics Department, and Science and Technology Unit, Umm-al-Qura University	RCV001263488	SCV001422490	pathogenic	Colon cancer	2018-10-06	flagged submission	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.
Molecular Biology Laboratory, Fundació Puigvert	RCV000195797	SCV001425220	likely pathogenic	Autosomal recessive polycystic kidney disease	2020-02-01	flagged submission	research
Natera, Inc.	RCV000195797	SCV001453262	uncertain significance	Autosomal recessive polycystic kidney disease	2017-05-07	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000587211	SCV001553362	uncertain significance	not provided		no assertion criteria provided	clinical testing