Submissions for variant NM_138694.4(PKHD1):c.8606C>A (p.Thr2869Lys)

gnomAD frequency: 0.01047  dbSNP: rs142522748

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000082586	SCV000114628	benign	not specified	2013-07-15	criteria provided, single submitter	clinical testing
Counsyl	RCV000169042	SCV000220200	likely benign	Autosomal recessive polycystic kidney disease	2014-03-27	criteria provided, single submitter	literature only
PreventionGenetics, part of Exact Sciences	RCV000082586	SCV000315846	benign	not specified		criteria provided, single submitter	clinical testing
Invitae	RCV000169042	SCV000557642	benign	Autosomal recessive polycystic kidney disease	2024-02-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587557	SCV000699883	likely benign	not provided	2016-01-22	criteria provided, single submitter	clinical testing	Variant summary: c.8606C>A affects a conserved nucleotide, resulting in amino acid change from Thr to Lys. 3/4 in-silico tools predict this variant to be damaging, however, these in silico predictions have not been validated by any in vitro/vivo functional studies yet. This variant was found in 1133/121106 control chromosomes at a frequency of 0.0093554, predominantly observed in non-Finnish European subpopulation in ExAC with MAF of 0.01445 (962/66572 chr) with total 14 homozygotes. This frequency exceeds the maximal expected frequency of a pathogenic allele (0.0070711), suggesting this variant is a benign polymorphism in non-Finnish Europeans. Two clinical laboratories via ClinVar classified this variant as benign/likely benign. Autosomal Recessive Polycystic Kidney Disease database and multiple literature publications list this variant as polymorphism. Considering all, this variant was classified as Likely Benign until more information becomes available.
SIB Swiss Institute of Bioinformatics	RCV000169042	SCV000803557	benign	Autosomal recessive polycystic kidney disease	2018-05-31	criteria provided, single submitter	curation	This variant is interpreted as a Benign, for Polycystic kidney disease 4 with or without polycystic liver disease, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: BS1 => Allele frequency is greater than expected for disorder. 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.
Illumina Laboratory Services, Illumina	RCV000169042	SCV001323389	likely benign	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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Laboratory of Molecular Diagnosis of Genetic Disease, Università degli Studi di Napoli Federico II	RCV001507101	SCV001712072	likely benign	Caroli disease	2021-05-05	criteria provided, single submitter	clinical testing
GeneDx	RCV000587557	SCV001888138	benign	not provided	2020-10-15	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 12874454, 15108277, 15805161, 15698423, 28492530, 12846734, 16133180, 25701400)
CeGaT Center for Human Genetics Tuebingen	RCV000587557	SCV002821377	benign	not provided	2024-03-01	criteria provided, single submitter	clinical testing	PKHD1: BS1, BS2
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001291891	SCV000592905	likely benign	Polycystic kidney disease		no assertion criteria provided	clinical testing	The PKHD1 p.Thr2869Lys variant was identified in 5 of 122 proband chromosomes (frequency: 0.041) from Spanish, American and British individuals or families with ARPKD/congenital hepatic fibrosis/Caroli’s disease, and was present in 5 of 420 control chromosomes (frequency: 0.012) from healthy individuals (Rosetti 2003, Furu 2004, Sharp 2005). Kindreds in which the variant was identified also carried multiple other variants, with at least one being pathogenic (Rosetti 2003). The variant was also identified in dbSNP (ID: rs142522748) “With likely benign allele”, Clinvitae database (classifications benign/likely benign), the ClinVar database (classification benign by Emory Genetics Laboratory, and likely benign by Counsyl), RWTH AAachen University ARPKD database (classified as a polymorphism) and PKHD1-LOVD (not classified); in the 1000 Genomes Project in 21 of 5000 chromosomes (frequency: 0.0042), HAPMAP populations EUR in 9 of 1006 chromosomes (frequency: 0.0089) and AMR in 12 of 694 chromosomes (frequency: 0.0173), NHLBI GO Exome Sequencing Project in 115 of 8600 European American alleles (frequency: 0.0134) and in 8 of 4406 African American alleles (frequency: 0.0018), and in the Exome Aggregation Consortium database (March 14, 2016) in 976 of 66572 chromosomes (frequency: 0.0145) from a population of European (Non-Finnish) individuals, and none in the East Asian, Other, African, Latino, South Asian, or European (Finnish) populations. The p.Thr2869 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not very predictive of pathogenicity. In summary, based on the above information, this variant meets our laboratory criteria to be classified as likely benign.
Natera, Inc.	RCV000169042	SCV002077974	benign	Autosomal recessive polycystic kidney disease	2017-05-11	no assertion criteria provided	clinical testing