Submissions for variant NM_001009944.3(PKD1):c.8020C>T (p.Pro2674Ser)

gnomAD frequency: 0.01150  dbSNP: rs144557371

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
PreventionGenetics, part of Exact Sciences	RCV000251247	SCV000305784	likely benign	not specified		criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000999801	SCV000604778	benign	Polycystic kidney disease, adult type	2020-04-04	criteria provided, single submitter	clinical testing
Athena Diagnostics Inc	RCV000755610	SCV001145013	benign	not provided	2019-03-18	criteria provided, single submitter	clinical testing
GeneDx	RCV000755610	SCV001911337	benign	not provided	2019-12-30	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 22008521, 17574468, 11115377, 32457805)
CeGaT Center for Human Genetics Tuebingen	RCV000755610	SCV002585539	benign	not provided	2024-01-01	criteria provided, single submitter	clinical testing	PKD1: BP4, BS1, BS2
Fulgent Genetics, Fulgent Genetics	RCV000999801	SCV002798483	likely benign	Polycystic kidney disease, adult type	2021-10-01	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001291879	SCV000592810	benign	Polycystic kidney disease		no assertion criteria provided	clinical testing	The PKD1 p.Pro2674Ser variant was identified in 11 of 586 proband chromosomes (frequency: 0.02) from individuals with Autosomal Dominant Polycystic Kidney Disease (Bataille 2011, Garcia-Gonzalez 2007, Rossetti 2001). The variant was identified in dbSNP (rs144557371) as “with other allele”, ClinVar (interpreted as likely benign by our laboratory and 1 other submitter; and as benign by ARUP Laboratories), LOVD 3.0 (observed 2x) and ADPKD Mutation Database (observed 1x). The variant was not identified in PKD1-LOVD. The variant was identified in control databases in 1570 of 151,230 chromosomes (10 homozygous) at a frequency of 0.01, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 26 of 13,758 chromosomes (freq: 0.002), Other in 52 of 4316 chromosomes (freq: 0.01), Latino in 155 of 24,266 chromosomes (freq: 0.006), European in 986 of 60,346 chromosomes (freq: 0.01), Ashkenazi Jewish in 58 of 7264 chromosomes (freq: 0.008), Finnish in 273 of 9002 chromosomes (freq: 0.03), and South Asian in 20 of 20,846 chromosomes (freq: 0.001); it was not observed in the East Asian population. 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 p.Pro2674 residue is not 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 outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) 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	RCV000251247	SCV001931058	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000251247	SCV001959789	benign	not specified		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000755610	SCV002037059	likely benign	not provided		no assertion criteria provided	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000251247	SCV003839844	benign	not specified	2022-07-12	no assertion criteria provided	clinical testing