Submissions for variant NM_001009944.3(PKD1):c.10225G>C (p.Val3409Leu)

gnomAD frequency: 0.04243  dbSNP: rs61747420

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
PreventionGenetics, part of Exact Sciences	RCV000251056	SCV000305661	benign	not specified		criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000755606	SCV000604736	benign	Polycystic kidney disease, adult type	2020-06-02	criteria provided, single submitter	clinical testing
GeneDx	RCV001682989	SCV001899319	benign	not provided	2019-10-11	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001291843	SCV000592842	benign	Polycystic kidney disease		no assertion criteria provided	clinical testing	The PKD1 p.Val3409Leu variant was identified in 7 of 698 proband chromosomes (frequency: 0.010) from individuals or families with ADPKD (Bataille 2011, Garcia-Gonzalez 2007, Rossetti 2012). The variant was identified in dbSNP (ID: rs61747420) as “NA”, ADPKD Mutation Database (classification likely neutral), but was not identified in Clinvitae, ClinVar, GeneInsight COGR, MutDB, PKD1-LOVD, and PKD1-LOVD 3.0. This variant was also identified in the 1000 Genomes Project in 257 of 5010 chromosomes (frequency: 0.05), HAPMAP-AFR in 246 of 1322 chromosomes (frequency: 0.1861) and HAPMAP-AMR in 11 of 694 chromosomes (frequency: 0.0159), NHLBI GO Exome Sequencing Project in 6 of 8521 European American alleles (frequency: 0.0007) and in 543 of 4370 African American alleles (frequency: 0.1242), and in the Exome Aggregation Consortium database (March 14, 2016) in 1418 of 112354 chromosomes (freq. 0.013) in the following populations: African in 1301 (84 homozygous) of 8808 chromosomes (freq. 0.15), Latino in 79 of 11296 chromosomes (freq. 0.007), other in 5 of 818 chromosomes (freq. 0.006), European (Non-Finish) in 32 of 60912 chromosomes (freq. 0.0005), and South Asian in 1 of 16374 chromosomes (freq. .00006), but was not seen in East Asian and Finish populations, increasing the likelihood that this may be a low frequency benign variant in certain populations of origin. The p.Val3409 residue is conserved in mammals and 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 5 bases from the 3’ splice site and 4 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict the abolishment of the consensus splice site. However, this information is not predictive enough to assume pathogenicity. 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	RCV000251056	SCV001931968	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000251056	SCV001959348	benign	not specified		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV001682989	SCV002036432	likely benign	not provided		no assertion criteria provided	clinical testing