Submissions for variant NM_001009944.3(PKD1):c.4015G>A (p.Val1339Met)

gnomAD frequency: 0.00024  dbSNP: rs147141131

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Fulgent Genetics, Fulgent Genetics	RCV000764035	SCV000894989	uncertain significance	Polycystic kidney disease, adult type	2018-10-31	criteria provided, single submitter	clinical testing
GeneDx	RCV003441897	SCV004167681	uncertain significance	not provided	2023-04-12	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
CeGaT Center for Human Genetics Tuebingen	RCV003441897	SCV005330277	uncertain significance	not provided	2024-07-01	criteria provided, single submitter	clinical testing	PKD1: PM2, BP4
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000500316	SCV000592768	uncertain significance	Polycystic kidney disease		no assertion criteria provided	clinical testing	The PKD1 p.Val1339Met variant was not identified in the literature nor was it identified in the Clinvitae, ClinVar, MutDB, GeneInsight COGR, PKD1-LOVD and PKD1-LOVD 3.0 databases. The variant was identified in dbSNP (ID: rs147141131) as “NA”; NHLBI GO Exome Sequencing Project in 4 of 8584 European American and not found in African American alleles. The variant was identified in Exome Aggregation Consortium database (March 14, 2016) in 20 of 116858 chromosomes (freq. 0.0001711) in the following populations: European (Non-Finnish) in 18 of 63996 chromosomes (freq. 0.0002813), East Asian in 1 of 8490 chromosomes (freq. 0.0001178), African in 1 of 9514 chromosomes (freq. 0.0001051), but was not seen in European (Finnish), Latino, South Asian and Other populations, increasing the likelihood this could be a low frequency benign variant. 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 also identified in ADPKD Mutation Database (classified as Likely Neutral and found with truncating variants and other more likely pathogenic missense mutations). The p.Val1339 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein. The variant occurs outside of the splicing consensus sequence and 3 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference splicing; a loss of a predicted splice site at a non-consensus splicing location. However, this information is not predictive enough to assume pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.