Submissions for variant NM_001009944.3(PKD1):c.2039A>T (p.Tyr680Phe)

gnomAD frequency: 0.00080  dbSNP: rs370141157

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
PreventionGenetics, part of Exact Sciences	RCV000242445	SCV000305705	likely benign	not specified		criteria provided, single submitter	clinical testing
Athena Diagnostics Inc	RCV000242445	SCV001475359	benign	not specified	2020-09-01	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001292234	SCV001481065	benign	Polycystic kidney disease		no assertion criteria provided	clinical testing	The PKD1 p.Tyr680Phe variant was identified in 2 of 98 proband chromosomes (frequency: 0.020) from individuals or families with ADPKD in the Chinese population. Family analysis showed that the variant does not co-segregate with ADPKD and was classified as a probable polymorphism (Liu 2015, Xiao-Ping 2012). The variant was also identified in dbSNP (ID: rs370141157) as “with likely benign allele”; in the Clinvitae and Clinvar databases (as likely benign by Prevention Genetics) and in ADPKD Mutation Database 2x as likely neutral. The variant was further identified in the 1000 Genomes Project in 16 of 5000 chromosomes (frequency: 0.0032); the genome Aggregation Database (February 27, 2017) in 217 of 237604 chromosomes (freq. 0.001); and in the Exome Aggregation Consortium database (August 8th 2016) in 73 of 33700 chromosomes (freq. 0.002) in the following populations: East Asian in 69 of 1894 chromosomes (freq. 0.036), South Asian in 2 of 8840 chromosomes (freq. 0.0002), European (Non-Finnish) in 1of 17664 chromosomes (freq. 0.0001), other in 1 of 280 chromosomes and not seen in the African and Finnish populations 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 variant was not identified in GeneInsight COGR, MutDB, PKD1-LOVD and PKD1-LOVD 3.0 databases and the NHLBI GO Exome Sequencing Project. In addition the variant was identified with a co-occurring pathogenic PKD2 variant (p.Arg803X), increasing the likelihood that the p.Tyr680Phe variant does not have clinical significance. The p.Tyr680 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 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) 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	RCV000242445	SCV001932847	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000242445	SCV001973073	benign	not specified		no assertion criteria provided	clinical testing