Submissions for variant NM_001009944.3(PKD1):c.974A>G (p.Tyr325Cys)

dbSNP: rs1232180956

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Blueprint Genetics	RCV000788578	SCV000927734	pathogenic	not provided	2018-06-08	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000788578	SCV001145025	pathogenic	not provided	2021-07-22	criteria provided, single submitter	clinical testing	This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. This variant associates with disease in multiple families. This variant occurs as the most likely explanation for disease in a significant number of internal cases, suggesting this variant is associated with disease. The variant is located in a region that is typically not considered important for protein function and/or structure. Computational tools predict that this variant is pathogenic.
Cavalleri Lab, Royal College of Surgeons in Ireland	RCV001095567	SCV001251198	uncertain significance	Polycystic kidney disease, adult type	2020-02-05	criteria provided, single submitter	research	PM2, PP3, PP4, PP5
GeneDx	RCV000788578	SCV002759179	uncertain significance	not provided	2022-06-01	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25475747, 17582161, 27499327, 33639313, 23431072, 22508176, 33454723)
Molecular Genetics of Inherited Kidney Disorders Laboratory, Garvan Institute of Medical Research	RCV004760785	SCV005373724	likely pathogenic	Autosomal dominant polycystic kidney disease	2024-06-05	criteria provided, single submitter	research
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV001095567	SCV005416771	likely pathogenic	Polycystic kidney disease, adult type		criteria provided, single submitter	clinical testing	PM2_Supporting+PS4+PP4
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001292501	SCV001481110	uncertain significance	Polycystic kidney disease		no assertion criteria provided	clinical testing	The PKD1 p.Tyr325Cys variant was identified in 7 of 3286 proband chromosomes (frequency: 0.002) from individuals or families with ADPKD (Audrézet 2012, Rossetti 2007, Cornec-Le Gall 2013). The variant was also identified in LOVD 3.0 (1x), and in the ADPKD Mutation Database (as Highly Likely Pathogenic). The variant was not identified in dbSNP, ClinVar, or PKD1-LOVD. The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The p.Tyr325 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of 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. This variant is classified as a variant of uncertain significance.