ClinVar Miner

Submissions for variant NM_001009944.3(PKD1):c.2534T>C (p.Leu845Ser) (rs199476100)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000712602 SCV000843119 pathogenic not provided 2017-11-29 criteria provided, single submitter clinical testing
Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota RCV000761309 SCV000891289 likely pathogenic Polycystic kidney disease 3 2018-03-28 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000008689 SCV000894071 pathogenic Polycystic kidney disease, adult type 2018-10-31 criteria provided, single submitter clinical testing
Blueprint Genetics RCV000712602 SCV000928064 pathogenic not provided 2018-11-20 criteria provided, single submitter clinical testing
Cavalleri Lab, Royal College of Surgeons in Ireland RCV000008689 SCV001251270 likely pathogenic Polycystic kidney disease, adult type 2020-02-05 criteria provided, single submitter research PS1, PP3, PP4
Molecular Biology Laboratory, Fundació Puigvert RCV000008689 SCV001425172 likely pathogenic Polycystic kidney disease, adult type 2020-02-01 criteria provided, single submitter research
OMIM RCV000008689 SCV000028898 pathogenic Polycystic kidney disease, adult type 1999-07-01 no assertion criteria provided literature only
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001292482 SCV001480590 likely pathogenic Polycystic kidney disease no assertion criteria provided clinical testing The PKD1 p.Leu845Ser variant was identified in 4 of 346 proband chromosomes (frequency: 0.012) from individuals or families of Chinese and Finnish ethnicity with ADPKD and was not identified in 420 control chromosomes from healthy individuals (Audrezet 2015, Liu 2015, Peltola 2005, Thomas 1999). Thomas et al (1999) identified the p.Leu845Ser variant in one affected individual and was not identified in the patient’s unaffected daughter. The variant was also identified in dbSNP (ID: rs199476100) as “With Pathogenic allele”, ClinVar database as pathogenic by OMIM and in ADPKD Mutation Database as highly likely pathogenic. The variant was not identified in GeneInsight-COGR, LOVD 3.0, PKD1-LOVD, databases nor was it identified in the 1000 Genomes and the NHLBI GO Exome Sequencing Projects. The variant was identified in control databases in 1 of 226770 chromosomes at a frequency of 0.000004 (Genome Aggregation Consortium Feb 27, 2017). In addition we cannot be certain that data from control databases is specific to PKD1 and not from one of the six PKD1 pseudogenes. The p.Leu845Ser residue is conserved in mammals but not in more distantly related organisms and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the p.Leu845Ser variant may impact the protein. However, this information is not predictive enough to assume pathogenicity. The variant predicts a change from a neutral and hydrophobic Leu to a polar Ser at position 845, six residues N-terminal to the start of PKD domain 2 (Thomas 1999). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The variant is located within the Polycystin cation channel functional domain increasing the likelihood that it may have clinical significance. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic.

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