Submissions for variant NM_138694.4(PKHD1):c.9866G>T (p.Ser3289Ile)

gnomAD frequency: 0.00287  dbSNP: rs148932323

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000153703	SCV000203261	benign	not specified	2016-04-06	criteria provided, single submitter	clinical testing
Counsyl	RCV000169100	SCV000220290	likely benign	Autosomal recessive polycystic kidney disease	2014-05-01	criteria provided, single submitter	literature only
Invitae	RCV000169100	SCV000255211	benign	Autosomal recessive polycystic kidney disease	2024-01-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000489179	SCV000577808	likely benign	not provided	2020-10-02	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 15805161, 21228398, 15108277)
Genetic Services Laboratory, University of Chicago	RCV000153703	SCV000596429	likely benign	not specified	2016-08-23	criteria provided, single submitter	clinical testing
Mendelics	RCV000169100	SCV001137137	benign	Autosomal recessive polycystic kidney disease	2019-05-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000489179	SCV001154766	likely benign	not provided	2022-11-01	criteria provided, single submitter	clinical testing	PKHD1: BS2
Illumina Laboratory Services, Illumina	RCV000169100	SCV001323267	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.
Genome-Nilou Lab	RCV001449953	SCV001653484	uncertain significance	Polycystic kidney disease 4	2021-05-18	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000489179	SCV001714168	uncertain significance	not provided	2020-05-14	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003907452	SCV004722245	likely benign	PKHD1-related disorder	2022-07-06	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001292034	SCV001480651	benign	Polycystic kidney disease		no assertion criteria provided	clinical testing	The PKHD1 p.Ser3289Ile variant was identified in 1 of 118 proband chromosomes (freq: 0.008) of individuals with autosomal recessive polycystic kidney disease (Sharp 2005). The variant was identified in dbSNP (rs148932323) as “with likely pathogenic allele”, ClinVar (interpreted as "likely benign" by Counsyl and 1 other, "benign" by Invitae and 1 other and "likely pathogenic" by GeneDx) and LOVD 3.0 (observed 6x). The variant was identified in control databases in 871 of 275,506 chromosomes (3 homozygous) at a frequency of 0.003 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 26 of 23,974 chromosomes (freq: 0.001), Other in 29 of 6406 chromosomes (freq: 0.005), Latino in 83 of 34,232 chromosomes (freq: 0.002), European in 599 of 125770 chromosomes (freq: 0.005), Ashkenazi Jewish in 1 of 10110 chromosomes (freq: 0.0001), Finnish in 120 of 25,664 chromosomes (freq: 0.004676), and South Asian in 13 of 30562 chromosomes (freq: 0.0005). The variant was not observed in the East Asian population. The p.Ser3289 residue is 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 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information this variant meets our laboratory criteria to be classified as benign. Assessment Date: 2019/08/09
Laboratory of Gastroenterology and Hepatology, Radboud University Medical Center	RCV001844809	SCV001876969	uncertain significance	Autosomal dominant polycystic liver disease	2021-09-01	no assertion criteria provided	research
Natera, Inc.	RCV000169100	SCV002075533	benign	Autosomal recessive polycystic kidney disease	2017-06-30	no assertion criteria provided	clinical testing