Submissions for variant NM_138694.4(PKHD1):c.9788T>C (p.Val3263Ala)

gnomAD frequency: 0.00261  dbSNP: rs146519878

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000153705	SCV000203263	likely benign	not specified	2016-04-04	criteria provided, single submitter	clinical testing
Invitae	RCV000196023	SCV000255210	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	RCV000153705	SCV000919988	uncertain significance	not specified	2017-10-16	criteria provided, single submitter	clinical testing	Variant summary: The PKHD1 c.9788T>C (p.Val3263Ala) variant causes a missense change involving the alteration of a conserved nucleotide. 2/3 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 463/258028 control chromosomes (gnomAD), including 2 homozygotes, at a frequency of 0.0017944, which does not exceed the estimated maximal expected allele frequency of a pathogenic PKHD1 variant (0.0070711). Clinical diagnostic laboratories/reputable databases classified this variant as likely benign and uncertain significance. The variant of interest has been reported in multiple patients with ARPKD (Melchionda_2016, Sharp_2005) and pathologies with partially overlapping renal phenotype, including one patient with dominantly inherited isolated polycystic liver disease (Besse_2017), all without strong evidence for causality. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until more definitive clinical and functional data become available.
Illumina Laboratory Services, Illumina	RCV000196023	SCV001324925	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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
GeneDx	RCV001572539	SCV001797198	likely benign	not provided	2020-08-23	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 21228398, 15805161)
CeGaT Center for Human Genetics Tuebingen	RCV001572539	SCV004700454	likely benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing	PKHD1: BP4
PreventionGenetics, part of Exact Sciences	RCV003937433	SCV004756311	likely benign	PKHD1-related condition	2022-02-09	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001292125	SCV001480625	uncertain significance	Polycystic kidney disease		no assertion criteria provided	clinical testing	The PKHD1, p.Val3263Ala variant was identified in 2 of 274 proband chromosomes (frequency: 0.007) from individuals or families with ARPKD, and was not identified in 200 control chromosomes from healthy individuals (Sharp 2005, Gunay-Aygun 2010). The variant was also identified in dbSNP (ID: rs146519878) as “With Uncertain significance allele”, Clinvitae database (classified as unclassified variant by ClinVar and Invitae), the ClinVar database (classified as uncertain significance by Emory Genetics and Invitae), RWTH AAachen University ARPKD database (classified as probably benign) and PKHD1-LOVD (2x as unknown/not classified). This variant was identified in the 1000 Genomes Project in 6 of 5000 chromosomes (frequency: 0.0012), the NHLBI GO Exome Sequencing Project in 25 of 8600 European American and in 1 of 4406 African American alleles, the Exome Aggregation Consortium database (August 8, 2016) in 210 (1 homozygous) of 121276 chromosomes (freq. 0.002) in the following populations: European in 193 of 66708 chromosomes (freq. 0.003), Latino in 7 of 11500 chromosomes (freq. 0.0006), African in 5 of 10406 chromosomes (freq. 0.0005), Finnish in 3 of 6612 chromosomes (freq. 0.0005), South Asian in 1 of 16512 chromosomes (freq. 0.00006), Other in 1 of 906 chromosomes (freq. 0.001), although this low number of observations and low frequency is not substantive enough to determine the prevalence of the variant in the general population and its relationship to disease. The p.Val3263 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 4 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict the loss of a 5’ splice site that is not at the canonical 5’ splice site. However, this information is not predictive enough to assume pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Laboratory of Gastroenterology and Hepatology, Radboud University Medical Center	RCV001844810	SCV001876970	uncertain significance	Autosomal dominant polycystic liver disease	2021-09-01	no assertion criteria provided	research