ClinVar Miner

Submissions for variant NM_001009944.3(PKD1):c.11249G>A (p.Arg3750Gln) (rs1327414405)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Blueprint Genetics RCV000788943 SCV000928243 pathogenic not provided 2019-02-21 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000788943 SCV001248131 pathogenic not provided 2019-12-01 criteria provided, single submitter clinical testing
Cavalleri Lab, Royal College of Surgeons in Ireland RCV001095597 SCV001251232 uncertain significance Polycystic kidney disease, adult type 2020-02-05 criteria provided, single submitter research PM5, PP3, PP4, PP5
Molecular Genetics of Inherited Kidney Disorders Laboratory,Garvan Institute of Medical Research RCV001254256 SCV001430296 likely pathogenic Autosomal dominant polycystic kidney disease 2019-01-01 criteria provided, single submitter research
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001292160 SCV001480761 uncertain significance Polycystic kidney disease no assertion criteria provided clinical testing The PKD1 p.Arg3750Gln variant was identified in 5 of 1474 proband chromosomes (frequency: 0.003) from French individuals or families with ADPKD (Audrezet 2012, Bataille 2011). Three of the affected individuals carried the c.11249_11250delinsAA, while one affected individual carried the c.11249G>A variant, both with the p.Arg3750Gln consequence (Audrezet 2012, Bataille 2011). The variant was also identified in ADPKD Mutation Database (classified highly likely pathogenic), and was not identified in dbSNP, ClinVar, LOVD 3.0, and PKD1-LOVD. The variant was identified in control databases in 1 of 243168 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017), observed in the following population: Ashkenazi Jewish in 1 of 9768 chromosomes (freq: 0.0001); it was not observed in the African, Other, Latino, European Non-Finnish, East Asian, Finnish, and South Asian populations. The p.Arg3750 residue is conserved across mammals and other organisms, and four out of five 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 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. 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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