Submissions for variant NM_001009944.3(PKD1):c.8444C>T (p.Ala2815Val)

gnomAD frequency: 0.00025  dbSNP: rs183084156

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics	RCV000516556	SCV000614549	benign	not specified	2017-05-03	criteria provided, single submitter	clinical testing
GeneDx	RCV001569140	SCV001793145	likely benign	not provided	2020-04-15	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 31730820, 24575920, 22185115, 31030424, 27567292)
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001292190	SCV001480914	likely benign	Polycystic kidney disease		no assertion criteria provided	clinical testing	The PKD1 p.Ala2815Val variant was identified in 3 of 430 proband chromosomes (frequency: 0.007) from individuals or families with ADPKD and was present in 3 of 500 control chromosomes (frequency: 0.006) from healthy individuals (Hirota 2016, Yu 2011). The variant was also identified in dbSNP (ID: rs183084156) as "With Benign allele", ClinVar (classified as benign by Athena Diagnostics), and in ADPKD Mutation Database (as likely neutral). The variant was not identified in LOVD 3.0 or PKD1-LOVD. The variant was identified in control databases in 123 of 275604 chromosomes at a frequency of 0.0005 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: Other in 1 of 6432 chromosomes (freq: 0.0002), European in 2 of 125478 chromosomes (freq: 0.00002), East Asian in 119 of 18844 chromosomes (freq: 0.006), and South Asian in 1 of 30774 chromosomes (freq: 0.00003), but was not observed in the African, Latino, Ashkenazi Jewish, and Finnish, populations. 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 also identified in two cases with a co-occurring pathogenic PKD1 variant (c.856_862del p.Gly287* and c.8470C>T p.Gln2824*) in our laboratory and with PKD1 variant (c.12444G>A Glu4148fs, Yu 2014), increasing the likelihood that the p.Ala2815Val variant does not have clinical significance. The p.Ala2815 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 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.