Submissions for variant NM_138694.4(PKHD1):c.9415G>T (p.Asp3139Tyr)

gnomAD frequency: 0.00407  dbSNP: rs45503297

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000153707	SCV000203265	likely benign	not specified	2015-03-16	criteria provided, single submitter	clinical testing
Counsyl	RCV000169053	SCV000220213	likely benign	Autosomal recessive polycystic kidney disease	2014-04-09	criteria provided, single submitter	literature only
Labcorp Genetics (formerly Invitae), Labcorp	RCV000169053	SCV000262501	benign	Autosomal recessive polycystic kidney disease	2024-01-31	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000153707	SCV000315853	likely benign	not specified		criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000169053	SCV000743913	likely benign	Autosomal recessive polycystic kidney disease	2017-02-01	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000169053	SCV000745353	likely benign	Autosomal recessive polycystic kidney disease	2015-08-18	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000169053	SCV001327183	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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000153707	SCV001361892	benign	not specified	2019-01-14	criteria provided, single submitter	clinical testing	Variant summary: PKHD1 c.9415G>T (p.Asp3139Tyr) results in a non-conservative amino acid change located in the right handed beta helix domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0041 in 277424 control chromosomes, predominantly at a frequency of 0.0075 within the Finnish subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within Finnish control individuals in the gnomAD database is approximately 1.061 fold of the estimated maximal expected allele frequency for a pathogenic variant in PKHD1 causing Polycystic Kidney and Hepatic Disease phenotype (0.0071), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Finnish origin. c.9415G>T has been reported in the literature in individuals affected with Polycystic Kidney and Hepatic Disease (Bergmann_2005, Furu_2003, Gunay-Aygun_2010, Losekoot_2005, Onuchi_2002, rossetti_2003, Ward_2002), however, authors predominantly refer to the variant as a polymorphism. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely benign/benign. Based on the evidence outlined above, the variant was classified as benign.
Genome-Nilou Lab	RCV001449939	SCV001653395	likely benign	Polycystic kidney disease 4	2021-05-18	criteria provided, single submitter	clinical testing
GeneDx	RCV001706025	SCV001881833	benign	not provided	2020-02-12	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 12874454, 26990548, 11898128, 21228398)
CeGaT Center for Human Genetics Tuebingen	RCV001706025	SCV003917060	likely benign	not provided	2023-05-01	criteria provided, single submitter	clinical testing	PKHD1: BP4, BS2
Molecular Genetics, Royal Melbourne Hospital	RCV000169053	SCV004812532	likely benign	Autosomal recessive polycystic kidney disease	2023-09-04	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001292335	SCV001480639	benign	Polycystic kidney disease		no assertion criteria provided	clinical testing	The PKHD1 p.Asp3139Tyr variant was identified in 6 of 888 proband chromosomes (frequency: 0.007) from individuals or families with ARPKD and was present in 13 of 1440 control chromosomes (frequency: 0.009) from healthy individuals (Bergmann 2004, Bergmann 2005, Gunay-Aygun 2010, Losekoot 2005, Rosetti 2003, Sharp 2005). The variant was also identified in dbSNP (ID: rs45503297) as "With other allele", ClinVar (classified as benign by Invitae; and as likely benign by Prevention Genetics, Counsyl, and three other submitters), LOVD 3.0 (4x as likely benign), and in RWTH AAachen University ARPKD database (as polymorphism). The variant was identified in control databases in 1133 of 276504 chromosomes (4 homozygous) at a frequency of 0.004, 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 27 of 24022 chromosomes (freq: 0.001), Other in 19 of 6456 chromosomes (freq: 0.003), Latino in 34 of 34376 chromosomes (freq: 0.0009), European in 757 of 126108 chromosomes (freq: 0.006), Ashkenazi Jewish in 9 of 10126 chromosomes (freq: 0.001), Finnish in 193 of 25786 chromosomes (freq: 0.007), and South Asian in 94 of 30780 chromosomes (freq: 0.003), while the variant was not observed in the East Asian population. The p.Asp3139 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 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.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV001706025	SCV002036913	likely benign	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV000169053	SCV002077946	benign	Autosomal recessive polycystic kidney disease	2017-05-23	no assertion criteria provided	clinical testing