Submissions for variant NM_138694.4(PKHD1):c.5896C>T (p.Leu1966=)

gnomAD frequency: 0.03202  dbSNP: rs1266923

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000082564	SCV000114606	benign	not specified	2013-04-23	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000082564	SCV000315815	benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000314583	SCV000464077	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000589675	SCV000699870	benign	not provided	2016-04-27	criteria provided, single submitter	clinical testing	Variant summary: The c.5896C>T variant involves the alteration of a conserved nucleotide resulting in a synonymous change. 4/5 in silico tools via Alamut predict no significant effect on splicing. The variant was observed in the large and broad cohorts of the ExAC project at an allele frequency of 3.2%, predominantly observed in the African subpopulation at a frequency of 13.5% including 82 homozygous occurrences. This frequency exceeds the maximal expected allele frequency for a pathogenic variant in PKHD1 (0.71%), suggesting this is a benign polymorphism found primarily in population(s) of African origin. Publications and a clinical lab have classifed the variant as polymorphism/benign.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000314583	SCV000743914	benign	Autosomal recessive polycystic kidney disease	2014-12-01	criteria provided, single submitter	clinical testing
Invitae	RCV000314583	SCV000754662	benign	Autosomal recessive polycystic kidney disease	2024-02-01	criteria provided, single submitter	clinical testing
Pars Genome Lab	RCV001530422	SCV001745243	benign	Polycystic kidney disease 4	2021-06-19	criteria provided, single submitter	clinical testing
GeneDx	RCV000589675	SCV001751499	benign	not provided	2018-07-09	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001291855	SCV000592898	benign	Polycystic kidney disease		no assertion criteria provided	clinical testing	The PKHD1 p.Leu1966Leu variant was identified in 2 of 726 proband chromosomes (frequency: 0.003) from individuals or families with ARPKD, and was present in 22 of 920 control chromosomes (frequency: 0.024) from healthy individuals (Bergmann 2005, Furu 2004, Losekoot 2005, Sharp 2005). The variant was also identified in dbSNP (ID: rs1266923) “With benign allele”, in 1000 Genomes Project in 408 of 5006 chromosomes (frequency: 0.0815), in NHLBI GO Exome Sequencing Project in 35 of 8600 (frequency: 0.004) European American and 586 in 4406 (frequency: 0.1285) African American alleles. This variant was identified in the Exome Aggregation Consortium database (March 14, 2016) in 3934 of 121262 chromosomes (frequency: 0.03) from a population (frequency) of African (0.14), East Asian (0.11), Finnish (0.06), South Asian (0.04), Other (0.03), Latino (0.02), and European Non-Finnish (0.006) individuals. Furthermore, the variant is listed in the ClinVar database as benign by Emory Genetics Laboratory, in the GeneInsight COGR database as benign by LMM, and in RWTH Aachen University ARPKD database as a polymorphism. The p.Leu1966Leu variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. 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 is classified as benign.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000314583	SCV000734506	benign	Autosomal recessive polycystic kidney disease		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000082564	SCV002036226	benign	not specified		no assertion criteria provided	clinical testing
Natera, Inc.	RCV000314583	SCV002078063	benign	Autosomal recessive polycystic kidney disease	2017-05-11	no assertion criteria provided	clinical testing