Submissions for variant NM_138694.4(PKHD1):c.6777C>T (p.Phe2259=)

gnomAD frequency: 0.00482  dbSNP: rs140065359

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000153712	SCV000203270	benign	not specified	2014-01-17	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000336710	SCV000464072	uncertain significance	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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Invitae	RCV000336710	SCV000557639	benign	Autosomal recessive polycystic kidney disease	2024-01-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000153712	SCV000918003	benign	not specified	2017-12-21	criteria provided, single submitter	clinical testing	Variant summary: The PKHD1 c.6777C>T (p.Phe2259Phe) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant. 4/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may affect ESE site of SC35. However, these predictions have yet to be confirmed by functional studies. This variant was found in 1516/276908 control chromosomes (12 homozygotes), predominantly observed in the European (Finnish) subpopulation at a frequency of 0.014629 (377/25770). This frequency is about 2 times the estimated maximal expected allele frequency of a pathogenic PKHD1 variant (0.0070711), suggesting this is likely a benign polymorphism found primarily in the populations of European (Finnish) origin. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. Taken together, by applying ACMG rules (BS1, BS2, BP6, BP7) this variant is classified as benign.
GeneDx	RCV001555451	SCV001776877	likely benign	not provided	2020-11-27	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001555451	SCV004011673	likely benign	not provided	2023-06-01	criteria provided, single submitter	clinical testing	PKHD1: BP4, BP7, BS2
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001292179	SCV001480828	benign	Polycystic kidney disease		no assertion criteria provided	clinical testing	The PKHD1 p.Phe2259= variant was identified in at least 1 of 252 proband chromosomes (frequency: 0.004) from individuals or families with ARPKD and was present in 1 of 400 control chromosomes (frequency: 0.0025) from healthy individuals (Bergmann_2005_15698423). The variant was also identified in dbSNP (ID: rs140065359) “With other allele”, ClinVar (classified with conflicting interpretations of pathogenicity; submitters: benign by EGL Genetic Diagnostics (Eurofins Clinical Diagnostics) and Invitae, and uncertain signficance by Illumina), and RWTH AAachen University ARPKD database (as unclassified); and not identified in GeneInsight-COGR and LOVD 3.0. The variant was identified in control databases in 1515 (12 homozygous) of 276508 chromosomes at a frequency of 0.005 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 13 of 24020 chromosomes (freq: 0.0005), Other in 41 (1 homozygous) of 6442 chromosomes (freq: 0.006), Latino in 84 of 34304 chromosomes (freq: 0.002), European Non-Finnish in 958 (8 homozygous) of 126228 chromosomes (freq: 0.008), Ashkenazi Jewish in 40 of 10134 chromosomes (freq: 0.004), European Finnish in 377 (3 homozygous) of 25770 chromosomes (freq: 0.01463), and South Asian in 2 of 30774 chromosomes (freq: 0.00007), and was not observed in the East Asian population. The p.Phe2259= 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. 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. In summary, based on the above information this variant meets our laboratory criteria to be classified as benign.
Natera, Inc.	RCV000336710	SCV002078043	benign	Autosomal recessive polycystic kidney disease	2017-05-11	no assertion criteria provided	clinical testing