Submissions for variant NM_001009944.3(PKD1):c.1583A>G (p.Tyr528Cys)

dbSNP: rs750798165

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
PreventionGenetics, part of Exact Sciences	RCV003403159	SCV004104609	pathogenic	PKD1-related disorder	2022-10-21	criteria provided, single submitter	clinical testing	The PKD1 c.1583A>G variant is predicted to result in the amino acid substitution p.Tyr528Cys. This variant has been reported in multiple unrelated individuals with polycystic kidney disease (Garcia-Gonzalez et al. 2007. PubMed ID: 17574468; Irazabal et al. 2011. PubMed ID: 21551026; Pei et al. 2012. PubMed ID: 22031115). At PreventionGenetics, we also found this variant previously in the heterozygous state in a patient tested for polycystic kidney disease. In vitro functional characterization suggests that this variant is deleterious (Pei et al. 2012. PubMed ID: 22031115). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005407657	SCV006072586	pathogenic	PKD1-Biallelic Autosomal Recessive Polycystic Kidney Disease	2025-04-08	criteria provided, single submitter	clinical testing	Variant summary: PKD1 c.1583A>G (p.Tyr528Cys) results in a non-conservative amino acid change located in the Polycystin cation channel domain (IPR006228) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. c.1583A>G has been reported in the literature in multiple individuals affected with Autosomal Dominant Polycystic Kidney Disease (Garcia-Gonzalez_2007, Pei_2012). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Pei_2012). The most pronounced variant effect results in formation of cysts and increased apoptosis in cells expressing this mutant protein. The following publications have been ascertained in the context of this evaluation (PMID: 17574468, 22031115). ClinVar contains an entry for this variant (Variation ID: 433946). Based on the evidence outlined above, the variant was classified as pathogenic.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000504528	SCV000592736	pathogenic	Autosomal dominant polycystic kidney disease		no assertion criteria provided	clinical testing	The PKD1 p.Tyr528Cys variant was identified in 2 of 1066 proband chromosomes (frequency: 0.002) from individuals or families with ADPKD (Garcia-Gonzalez 2007, Irazabal 2011). The variant was also identified in ADPKD Mutation Database (as highly likely pathogenic). The variant was not identified in dbSNP, Clinvitae, GeneInsight COGR, MutDB, PKD1-LOVD, PKD1-LOVD 3.0, NHLBI GO Exome Sequencing Project and Exome Aggregation Consortium database (March 14, 2016). The p.Tyr528 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. 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. In addition, an in vivo study by Pei (2012), demonstrated that the p.Tyr528Cys variant affects an amino acid residue in the C-type lectin domain of polycystin-1 (PC1) that is highly-conserved across multiple species and moderately conserved across non-PC1 proteins with the same domain. The data from the study strongly suggest that this variant is a pathogenic PKD1 variant and that it functions as a hypomorphic allele in-vivo. The cell lines expressing the p.Tyr528Cys variant formed cysts in culture and demonstrated increased rates of growth and apoptosis. However, subjects affected with p.Tyr528Cys (PKD1) and a truncating PKD2 variant (p.Leu736X) had more severe renal disease than subjects affected with a pathogenic PKD1 or PKD2 variant alone. The individuals with p.Tyr528Cys clearly had better preserved renal function and have uniformly mild renal disease. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.