Submissions for variant NM_138694.4(PKHD1):c.11714T>A (p.Ile3905Asn)

gnomAD frequency: 0.04490  dbSNP: rs2661488

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000082523	SCV000114565	benign	not specified	2016-02-04	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000082523	SCV000315765	benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000321817	SCV000464023	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.
Invitae	RCV000321817	SCV000557649	benign	Autosomal recessive polycystic kidney disease	2024-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV001705790	SCV001832964	benign	not provided	2018-07-09	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001292299	SCV001480578	benign	Polycystic kidney disease		no assertion criteria provided	clinical testing	The PKHD1 p.Ile3905Asn variant was identified in dbSNP (ID: rs2661488) “With other allele” and in control databases in 7988 of 276978 chromosomes (184 homozygous) at a frequency of 0.03 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 2274 (102 homozygous) of 24016 chromosomes (freq: 0.09), Other in 143 of 6456 chromosomes (freq: 0.02), Latino in 1011 (17 homozygous) of 34356 chromosomes (freq: 0.03), European Non-Finnish in 3354 (43 homozygous) of 126578 chromosomes (freq: 0.03), Ashkenazi Jewish in 285 (5 homozygous) of 10144 chromosomes (freq: 0.03), East Asian in 7 of 18856 chromosomes (freq: 0.0004), European Finnish in 299 (3 homozygous) of 25790 chromosomes (freq: 0.01), and South Asian in 615 (14 homozygous) of 30782 chromosomes (freq: 0.02). The p.Ile3905Asn residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, 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, 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.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000082523	SCV002033920	benign	not specified		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000082523	SCV002036752	benign	not specified		no assertion criteria provided	clinical testing
Natera, Inc.	RCV000321817	SCV002075471	benign	Autosomal recessive polycystic kidney disease	2017-05-11	no assertion criteria provided	clinical testing