Submissions for variant NM_138694.4(PKHD1):c.9577G>A (p.Val3193Ile)

gnomAD frequency: 0.01835  dbSNP: rs35445653

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000204043	SCV000260375	benign	Autosomal recessive polycystic kidney disease	2024-01-31	criteria provided, single submitter	clinical testing
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000224330	SCV000281399	benign	not provided	2015-09-29	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000242191	SCV000315854	benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000204043	SCV000464040	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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000224330	SCV000699887	benign	not provided	2016-08-09	criteria provided, single submitter	clinical testing	Variant summary: The PKHD1 c.9577G>A (p.Val3193Ile) variant involves the alteration of a non-conserved nucleotide. 4/4 in silico tools predict a benign outcome for this variant. This variant was found in 720/121508 control chromosomes (including 12 homozygotes), predominantly observed in the African subpopulation at a frequency of 0.0612736 (637/10396). This frequency is about 9 times the estimated maximal expected allele frequency of a pathogenic PKHD1 variant (0.0070711). As this variant exceeds allele frequency of 5% in African population, it can be regarded a common benign polymorphism found in the populations of African origin. It has also been published as a polymorphism in literature from in a ARPKD patient/normal controls (Sharp_2005). In addition, multiple clinical diagnostic laboratories have classified this variant as benign. Taken together, this variant is classified as Benign.
GeneDx	RCV000224330	SCV001897380	benign	not provided	2020-06-23	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 15698423)
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001292516	SCV001480649	benign	Polycystic kidney disease		no assertion criteria provided	clinical testing	The PKHD1 p.Val3193Ile variant was identified in 2 of 446 proband chromosomes (frequency: 0.004) from individuals with autosomal recessive polycystic kidney disease and 5 of 600 chromosomes (frequency: 0.008) from health individuals (Sharp 2005, Bergmann 2005). The variant was identified in dbSNP (rs35445653) as “other allele”, ClinVar (classified as benign by Invitae, Integrated Genetics, Prevention Genetics and Children Mercy Hospital and likely benign by Illumina) an LOVD 3.0 (observed 2x). The variant was identified in control databases in 1787 of 282,242 chromosomes (38 homozygous) at a frequency of 0.006 (Genome Aggregation Database Feb 27, 2017) increasing the likelihood this could be a low frequency benign variant. The variant was observed in the following populations: African in 1522 of 24,938 chromosomes (freq: 0.06), Latino in 165 of 35,380 chromosomes (freq: 0.005), Other in 26 of 7208 chromosomes (freq: 0.004), South Asian in 11 of 30,616 chromosomes (freq: 0.0004), European in 57 of 128,682 chromosomes (freq: 0.0004), and East Asian in 6 of 19,946 chromosomes (freq: 0.0003); it was not observed in the Ashkenazi Jewish or Finnish populations. The p.Val3193 residue is conserved in in mammals but not in more distantly related organisms however computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) 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)	RCV000242191	SCV001800618	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000242191	SCV001926912	benign	not specified		no assertion criteria provided	clinical testing
Natera, Inc.	RCV000204043	SCV002077944	benign	Autosomal recessive polycystic kidney disease	2017-06-30	no assertion criteria provided	clinical testing