Submissions for variant NM_138694.4(PKHD1):c.11340T>C (p.Pro3780=)

gnomAD frequency: 0.03744  dbSNP: rs17667728

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
PreventionGenetics, part of Exact Sciences	RCV000243640	SCV000315760	benign	not specified		criteria provided, single submitter	clinical testing
Invitae	RCV000475277	SCV000557658	benign	Autosomal recessive polycystic kidney disease	2024-02-01	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000475277	SCV000743912	benign	Autosomal recessive polycystic kidney disease	2014-10-10	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000475277	SCV001324809	benign	Autosomal recessive polycystic kidney disease	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
GeneDx	RCV001539758	SCV001757564	likely benign	not provided	2020-09-16	criteria provided, single submitter	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000475277	SCV000734505	benign	Autosomal recessive polycystic kidney disease		no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001292298	SCV001480577	benign	Polycystic kidney disease		no assertion criteria provided	clinical testing	The PKHD1 p.Pro3780= variant was identified in dbSNP (ID: rs17667728) as “With Benign allele”, ClinVar (as benign by Prevention Genetics and Invitae), Clinvitae (3x as benign), RWTH AAachen University ARPKD database (as a polymorphism). The variant was not identified in the LOVD 3.0 database. The variant was also identified in control databases in 9157 of 276782 chromosomes at a frequency of 0.033084 in the following populations at a frequency greater than 1%: African in 1053 (29 homozygous) of 24034 chromosomes (freq. 0.044), Other in 222 (1 homozygous) of 6454 chromosomes (freq. 0.034), Latino in 1111 (24 homozygous) of 34410 chromosomes (freq. 0.032), European (Non-Finnish) in 5290 (109 homozygous) of 126334 chromosomes (freq. 0.042), Ashkenazi Jewish in 400 (8 homozygous) of 10134 chromosomes (freq. 0.039), European (Finnish) in 361 (5 homozygous) of 25782 chromosomes (freq. 0.014), and South Asian in 713 (20 homozygous) of 30778 chromosomes (freq. 0.023) as well as at frequencies below 1% in East Asian populations in 7 of 18856 chromosomes (freq. 0.0004) increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The variant is widely reported in the literature as a polymorphism, with an allele frequency between 3 and 5% (Bergmann 2004, Bergmann 2005, Furu 2003, Losekoot 2005, Obeidova 2015, Rosetti 2003, Sharp 2005). The p.Pro3780= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. 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)	RCV000243640	SCV002036196	benign	not specified		no assertion criteria provided	clinical testing
Natera, Inc.	RCV000475277	SCV002075486	benign	Autosomal recessive polycystic kidney disease	2017-05-11	no assertion criteria provided	clinical testing