ClinVar Miner

Submissions for variant NM_138694.4(PKHD1):c.9530T>C (p.Ile3177Thr) (rs200511261)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 8
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000444254 SCV000511084 pathogenic not provided 2017-01-06 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000502876 SCV000894382 likely pathogenic Autosomal recessive polycystic kidney disease 2018-10-31 criteria provided, single submitter clinical testing
Invitae RCV000502876 SCV000937398 uncertain significance Autosomal recessive polycystic kidney disease 2020-10-08 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 3177 of the PKHD1 protein (p.Ile3177Thr). The isoleucine residue is weakly conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is present in population databases (rs200511261, ExAC 0.007%). This variant has been observed on the same chromosome with another PKHD1 variant (p.Pro805Leu) in individuals affected with polycystic kidney disease (PMID: 16133180, 15108281, 18503009, 19940839). The haplotype (Pro805Leu; Ile3177Thr) has been observed on the opposite chromosome from other pathogenic variants in an individuals affected with polycystic kidney disease (PMID: 12846734, 15108281, Invitae). ClinVar contains an entry for this variant (Variation ID: 377018). 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: Deleterious; PolyPhen-2: Possibly Damaging; Align-GVGD: Class C0). 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.
Baylor Genetics RCV000502876 SCV001163019 pathogenic Autosomal recessive polycystic kidney disease criteria provided, single submitter clinical testing
Johns Hopkins Genomics, Johns Hopkins University RCV001336942 SCV001548523 likely pathogenic Polycystic kidney disease 4 2021-03-10 criteria provided, single submitter clinical testing This PKHD1 variant (rs200511261) is rare (<0.1%) in a large population dataset (gnomAD: 13/250878 total alleles; 0.005%; no homozygotes) and has an entry in ClinVar. It has been observed on the opposite chromosome from other pathogenic variants in individuals affected with PKD4. Two bioinformatics tools queried predict that p.Ile3177Thr would be tolerated, while another predicts it would be damaging. The isoleucine residue at this position is partially conserved across the vertebrate species assessed; some species have a valine substitution at this position. This variant is not predicted to affect normal exon 58 splicing, although this has not been confirmed experimentally to our knowledge. We consider c.9530T>C to be likely pathogenic.
Mayo Clinic Laboratories, Mayo Clinic RCV000444254 SCV001714170 likely pathogenic not provided 2019-11-25 criteria provided, single submitter clinical testing PM2, PM3, PP1, PP4, PP5
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000444254 SCV000592907 pathogenic not provided no assertion criteria provided clinical testing The PKHD1 p.Ile3177Thr variant was identified in 10 of 974 proband chromosomes (frequency: 0.01) from individuals or families with ARPKD (Bergmann 2005, Denamur 2010, Furu 2004, Gunay-Aygun 2010, Losekoot 2005, Rosetti 2003).The variant was also identified in dbSNP (ID: rs200511261), Clinvitae database (as pathogenic by Emory genetics) RWTH AAachen University ARPKD database (as pathogenic) and PKHD1-LOVD. This variant was identified in the NHLBI GO Exome Sequencing Project in 1 of 8600 European American alleles (freq. 0.0001) and Exome Aggregation Consortium database (March 14, 2016) in 5 of 66720 chromosomes (freq. 7.49E-05) in the European population, this low number of observations and low frequency is not substantive enough to determine the prevalence of the variant in the general population and its relationship to disease. The p.Ile3177 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. The case studies by Arbeiter (2008) and Denamur (2010) identify this mutation along with evolutionarily highly conserved missense change c.2414CT (p.Pro805Leu) in patients who died perinatally from ARPKD. In addition, several studies found the variant in patients with severe perinatally-fatal phenotype of ARPKD (Bergmann 2005, Furu 2004, Gunay-Aygun 2010, Rosetti 2003, Losekoot 2005). In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.
Gharavi Laboratory,Columbia University RCV000444254 SCV000920666 uncertain significance not provided 2018-09-16 no assertion criteria provided research

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.