ClinVar Miner

Submissions for variant NM_001009944.3(PKD1):c.3496G>A (p.Gly1166Ser) (rs573566419)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000507997 SCV000604791 likely pathogenic not provided 2018-04-17 criteria provided, single submitter clinical testing The PKD1 c.3496G>A, p.Gly1166Ser variant (rs573566419) has been reported in a patient diagnosed with autosomal dominant polycystic kidney disease (Phakdeekitcharoen 2000), and is considered likely pathogenic by the Mayo ADPKD variant database. It is observed at a low frequency of 0.004% (8/177768 alleles) in the Genome Aggregation Database, but is considered a low confidence variant in the database. The glycine at residue 1166 is highly conserved, but computational algorithms (PolyPhen-2: possibly damaging; SIFT: tolerated) are inconclusive on the variant's impact on the protein. Functional characterization of the variant in archaea ortholog of the PKD domain shows reduced thermodynamic and mechanical stability (Ma 2009), consistent with protein structure analyses predicting a disruption of the PKD domain (Ma 2009, Phakdeekitcharoen 2000). Based on the above information, the variant is classified as likely pathogenic. References: Mayo ADPKD variant database: Ma L et al. Naturally occurring mutations alter the stability of polycystin-1 polycystic kidney disease (PKD) domains. J Biol Chem. 2009; 284(47):32942-9. Phakdeekitcharoen B et al. Thirteen novel mutations of the replicated region of PKD1 in an Asian population. Kidney Int. 2000; 58(4):1400-12.
Mendelics RCV000989462 SCV001139793 uncertain significance Polycystic kidney disease, adult type 2019-05-28 criteria provided, single submitter clinical testing
GeneDx RCV000507997 SCV001777382 uncertain significance not provided 2020-11-06 criteria provided, single submitter clinical testing Published functional studies demonstrate a strong destabilizing effect on the protein (Ma et al., 2009); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31589614, 11012875, 25365220, 19759016)
Gharavi Laboratory,Columbia University RCV000507997 SCV000920750 uncertain significance not provided 2018-09-16 no assertion criteria provided research

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