Submissions for variant NM_138694.4(PKHD1):c.10515C>A (p.Ser3505Arg)

gnomAD frequency: 0.00721  dbSNP: rs139014478

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000153702	SCV000203260	benign	not specified	2014-01-17	criteria provided, single submitter	clinical testing
Invitae	RCV000204345	SCV000260345	benign	Autosomal recessive polycystic kidney disease	2024-01-31	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000153702	SCV000315754	benign	not specified		criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000153702	SCV000919992	benign	not specified	2019-11-05	criteria provided, single submitter	clinical testing	Variant summary: PKHD1 c.10515C>A (p.Ser3505Arg) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.007 in 281496 control chromosomes, predominantly at a frequency of 0.011 within the Non-Finnish European subpopulation in the gnomAD database, including 6 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.5 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. Though the variant, c.10515C>A, has been reported in the literature in individuals affected with Polycystic Kidney and Hepatic Disease, it has also been found in controls, and therefore multiple studies reported it as a polymorphism. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and both of them classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign.
Illumina Laboratory Services, Illumina	RCV000204345	SCV001323261	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.
GeneDx	RCV001574722	SCV001801591	likely benign	not provided	2021-02-23	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001574722	SCV004163590	benign	not provided	2024-03-01	criteria provided, single submitter	clinical testing	PKHD1: BP4, BS1, BS2
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001291892	SCV000592908	benign	Polycystic kidney disease		no assertion criteria provided	clinical testing	The PKHD1, p.Ser3505Arg variant was identified as a polymorphism in several studies (frequency information not specified) from Spanish, American and British individuals or families with ARPKD/congenital hepatic fibrosis/Caroli’s disease, and was present in 6 of 390 control chromosomes (frequency: 0.015) from healthy individuals (Rosetti 2003, Sharp 2005, Losekoot 2005). The variant was also identified in dbSNP (ID: rs139014478) “With benign allele”, Clinvitae database (classification benign), the ClinVar database (classification benign by Emory Genetics Laboratory and Invitae), RWTH AAachen University ARPKD database (classified as a polymorphism); in the 1000 Genomes Project in 22 of 5000 chromosomes (frequency: 0.0044), HAPMAP populations EUR in 11 of 1006 chromosomes (frequency: 0.0109) and AMR in 11 of 694 chromosomes (frequency: 0.0159), NHLBI GO Exome Sequencing Project in 97 of 8600 European American alleles (frequency: 0.0112) and in 10 of 4406 African American alleles (frequency: 0.0022), and in the Exome Aggregation Consortium database (March 14m 2016) in 695 of 66390 chromosomes/ 5 homozygous (frequency: 0.0104) from a population of European (Non-Finnish) individuals, in 68 of 11398 chromosomes/ 1 homozygous (frequency: 0.0104) from a population of Latino individuals and none in the East Asian, Other, African, South Asian, or European (Finnish) populations. The p.Ser3505 residue is mostly 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. In summary, based on the above information, this variant meets our laboratory criteria to be classified as benign.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000153702	SCV002034262	benign	not specified		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV001574722	SCV002035463	likely benign	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV000204345	SCV002075509	benign	Autosomal recessive polycystic kidney disease	2017-06-30	no assertion criteria provided	clinical testing