Submissions for variant NM_001009944.3(PKD1):c.8964G>A (p.Ala2988=)

gnomAD frequency: 0.00619  dbSNP: rs76184385

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
PreventionGenetics, part of Exact Sciences	RCV000242687	SCV000305811	benign	not specified		criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000999997	SCV000604809	benign	Polycystic kidney disease, adult type	2019-07-25	criteria provided, single submitter	clinical testing
Athena Diagnostics Inc	RCV000712667	SCV000843186	benign	not provided	2018-08-20	criteria provided, single submitter	clinical testing
GeneDx	RCV000712667	SCV001869147	benign	not provided	2021-01-05	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 10854095, 11558899, 12007219, 22383692, 22608885, 24374109)
CeGaT Center for Human Genetics Tuebingen	RCV000712667	SCV002585537	likely benign	not provided	2023-05-01	criteria provided, single submitter	clinical testing	PKD1: BP4, BP7, BS2
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001291917	SCV000592832	benign	Polycystic kidney disease		no assertion criteria provided	clinical testing	The PKD1 p.Ala2988Ala variant was identified in 9 of 1202 proband chromosomes (frequency: 0.007) from individuals or families with ADPKD (Perrichot 2000, Inoue 2002, Mizoguchi 2001, Rossetti 2012, Tan 2012, Tan 2014). The variant was also identified in dbSNP (ID: rs76184385) and ADPKD Mutation Database (as likely neutral). This variant was identified in the 1000 Genomes Project in 31 of 5000 chromosomes (frequency: 0.006), NHLBI GO Exome Sequencing Project in 54 of 8570 European American (freq. 0.006) and in 4 of 4374 of African American alleles (freq. 0.0009).The p.Ala2988Ala variant was also identified in Exome Aggregation Consortium database (March 14, 2016) in 837 (6 homozygous) of 118036 chromosomes (freq. 0.007) in the following populations: European in 412 of 64634 chromosomes (freq. 0.006), Finnish in 120 of 6556 chromosomes (freq. 0.02), Latino in 105 of 11458 chromosomes (freq. 0.009), East Asian in 100 of 8594 chromosomes (freq. 0.01), South Asian in 87 of 16494 chromosomes (freq. 0.005), African in 7 of 9428 chromosomes (freq. 0.0007) and Other in 6 of 872 chromosomes (freq. 0.007), 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 p.Ala2988Ala 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 1 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. Two population studies by Perrichot (2000) and Mizoguchi (2001) classified the variant as polymorphism since the variant does not lead to the modification of the encoded amino acid. In addition, another population study by Rossetti (2012) classified the variant as known exonic polymorphic variant. In addition, the variant was identified with a co-occurring pathogenic PKD1 variant in our lab (p.Ala3571_Val3572del), increasing the likelihood that the p.Ala2988Ala variant does not have clinical significance. In summary, based on the above information, this variant meets our laboratory criteria to be classified as benign.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000712667	SCV002035929	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000712667	SCV002038200	likely benign	not provided		no assertion criteria provided	clinical testing