Submissions for variant NM_138694.4(PKHD1):c.1185T>C (p.Asp395=)

gnomAD frequency: 0.96234  dbSNP: rs1896976

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000082524	SCV000114566	benign	not specified	2015-10-27	criteria provided, single submitter	clinical testing
Counsyl	RCV000169626	SCV000221155	benign	Autosomal recessive polycystic kidney disease	2015-02-24	criteria provided, single submitter	literature only
PreventionGenetics, part of Exact Sciences	RCV000082524	SCV000315767	benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000169626	SCV000464121	benign	Autosomal recessive polycystic kidney disease	2018-01-13	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	RCV000169626	SCV001000023	benign	Autosomal recessive polycystic kidney disease	2024-02-01	criteria provided, single submitter	clinical testing
Pars Genome Lab	RCV001530446	SCV001745274	benign	Polycystic kidney disease 4	2021-06-19	criteria provided, single submitter	clinical testing
GeneDx	RCV001705791	SCV001834888	benign	not provided	2018-07-09	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001530446	SCV002030001	benign	Polycystic kidney disease 4	2021-09-05	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001291927	SCV000592884	benign	Polycystic kidney disease		no assertion criteria provided	clinical testing	The PKHD1 p.Asp395= variant was identified in 29 of 258 proband chromosomes (frequency: 0.11) from individuals or families with ARPKD (Rossetti 2003, Losekoot 2005, Obeidova 2015). The variant was also identified in dbSNP (ID: rs1896976) as “With Benign allele”, ClinVar (4x, as benign, by EGL, Counsyl, Prevention Genetics, Illumina), RWTH AAachen University ARPKD database (115x, as polymorphism) databases. The variant was not identified in LOVD 3.0, databases. The variant was also identified by our laboratory in 19 individuals with ARPKD The variant was identified in control databases in 273534 of 276906 (135258 homozygous) chromosomes at a frequency of 0.987823 The variant was identified in the following populations at a frequency greater than 1%: African in 21039 of 24008 chromosomes (freq. 0.9), other in 6413 of 6458 chromosomes (freq. 0.99), Latino in 34151 of 34410 chromosomes (freq. 0.99), European in 126382 of 126462 chromosomes (freq. 0.99), Ashkenazi Jewish in 10130 of 10142 chromosomes (freq. 0.99), Eat Asian in 18862 of 18862 chromosomes (freq. 1), Finnish in 25784 of 25784 chromosomes (freq. 1),and South Asian in 30773 of 30784 chromosomes (freq. 0.99), increasing the likelihood this a benign variant (Genome Aggregation Consortium Feb 27, 2017). The p.Asp395Asp variant is not expected to have clinical significance because it does not result in a change of amino acid. The variant occurs outside of the splicing consensus sequence and 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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000082524	SCV001739803	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000082524	SCV001951852	benign	not specified		no assertion criteria provided	clinical testing
Natera, Inc.	RCV000169626	SCV002083377	benign	Autosomal recessive polycystic kidney disease	2017-05-11	no assertion criteria provided	clinical testing