ClinVar Miner

Submissions for variant NM_001009944.3(PKD1):c.974A>G (p.Tyr325Cys) (rs1232180956)

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Total submissions: 4
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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 Inc 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
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.

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