Submissions for variant NM_001009944.3(PKD1):c.8111C>T (p.Ala2704Val)

gnomAD frequency: 0.00059  dbSNP: rs200509641

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000507819	SCV000604759	likely benign	not specified	2016-12-02	criteria provided, single submitter	clinical testing
Athena Diagnostics Inc	RCV000712655	SCV000843174	benign	not provided	2018-06-08	criteria provided, single submitter	clinical testing
Molecular Genetics of Inherited Kidney Disorders Laboratory, Garvan Institute of Medical Research	RCV001254318	SCV001430270	likely benign	Autosomal dominant polycystic kidney disease	2019-01-01	criteria provided, single submitter	research
Fulgent Genetics, Fulgent Genetics	RCV002490855	SCV002797518	likely benign	Polycystic kidney disease, adult type	2021-11-02	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000712655	SCV004142845	likely benign	not provided	2023-03-01	criteria provided, single submitter	clinical testing	PKD1: BP4, BS2
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001292090	SCV001480856	likely benign	Polycystic kidney disease		no assertion criteria provided	clinical testing	The PKD1 p.Ala2704Val variant was identified in 1 of 74 proband chromosomes (frequency: 0.01) from individuals or families with ADPKD (Bataille 2011). The variant was also identified in dbSNP (ID: rs200509641), LOVD 3.0 (2X), and the ADPKD Mutation Database (likely neutral). The variant was not identified in ClinVar, COGR, or PKD1-LOVD databases. The variant was identified in control databases in 239 of 180276 chromosomes at a frequency of 0.001 in the following populations: South Asian in 125 of 23404 chromosomes (freq. 0.005), European in 70 of 73288 chromosomes (freq. 0.001), Finnish in 19 of 15662 chromosomes (freq. 0.001), Other in 8 of 4820 chromosomes (freq. 0.002), Latino in 7 of 25668 chromosomes (freq. 0.0003), East Asian in 4 of 13122 chromosomes (freq.0.0003), African in 3 of 15856 chromosomes (freq. 0.0002), Ashkenazi Jewish in 3 of 8466 chromosomes (freq. 0.0003), increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). In addition we cannot be certain that data from control databases is specific to PKD1 and not from one of the six PKD1 pseudogenes. This variant was also identified in one individual from our laboratory with a co-occurring pathogenic variant in PKD2 (c.1704dupT, p.Val569CysfsX4), increasing the likelihood this variant does not have clinical significance. The p.Ala2704 residue is not conserved in mammals and four out of five 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 2 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, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000712655	SCV001931570	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000712655	SCV001970979	likely benign	not provided		no assertion criteria provided	clinical testing