Submissions for variant NM_001009944.3(PKD1):c.4071G>T (p.Leu1357=)

gnomAD frequency: 0.00637  dbSNP: rs145737766

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
PreventionGenetics, part of Exact Sciences	RCV000253778	SCV000305736	benign	not specified		criteria provided, single submitter	clinical testing
Athena Diagnostics Inc	RCV000712621	SCV000843138	benign	not provided	2018-05-14	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000999993	SCV000885917	benign	Polycystic kidney disease, adult type	2020-04-20	criteria provided, single submitter	clinical testing
GeneDx	RCV000712621	SCV001776635	likely benign	not provided	2021-03-08	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 17574468, 22008521, 22383692)
CeGaT Center for Human Genetics Tuebingen	RCV000712621	SCV002545729	likely benign	not provided	2024-01-01	criteria provided, single submitter	clinical testing	PKD1: BP4, BP7, BS2
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001291896	SCV000592769	benign	Polycystic kidney disease		no assertion criteria provided	clinical testing	The PKD1 p.Leu1357Leu variant was identified in 8 of 698 proband chromosomes (frequency: 0.011) from individuals or families with ADPKD (Bataille 2011, Garcia-Gonzalez 2007, Rossetti 2012). The variant was also identified in dbSNP (ID: rs145737766) as “NA”, the ADPKD Mutation Database (as likely neutral), 1000 Genomes Project in 19 of 5000 chromosomes (frequency: 0.0038), the Exome Aggregation Consortium database (March 14, 2016) in 677 (11 homozygous) of 117978 chromosomes (freq. 0.006) in the following populations: European in 552 of 64394 chromosomes (freq. 0.009), Latino in 54 of 11464 chromosomes (freq. 0.005), South Asian in 45 of 16480 chromosomes (freq. 0.003), African in 13 of 9812 chromosomes (freq. 0.001), Finnish in 12 of 6442 chromosomes (freq. 0.002), Other in 1 of 8530 chromosomes (freq. 0.001), increasing the likelihood this could be a low frequency benign variant. In addition we cannot be certain that data from control databases is specific to PKD1 and not from one of the six PKD1 pseudogenes. The variant was not identified in Clinvitae, ClinVar, GeneInsight COGR, MutDB, PKD1-LOVD, and PKD1-LOVD 3.0. The p.Leu1357Leu 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. 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 addition, several PKD studies classify the variant as known exonic polymorphic variant (Bataille 2011, Garcia-Gonzalez 2007, Rossetti 2012). 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	RCV000253778	SCV002034145	benign	not specified		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000712621	SCV002036929	likely benign	not provided		no assertion criteria provided	clinical testing