ClinVar Miner

Submissions for variant NM_001009944.3(PKD1):c.11537+3_11537+5dup (rs201204878)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
PreventionGenetics,PreventionGenetics RCV000250913 SCV000305678 likely benign not specified criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000712583 SCV000843099 benign not provided 2017-10-11 criteria provided, single submitter clinical testing
Mendelics RCV000989447 SCV001139773 benign Polycystic kidney disease, adult type 2019-05-28 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000989447 SCV001158233 benign Polycystic kidney disease, adult type 2020-02-04 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001291847 SCV000592853 benign Polycystic kidney disease no assertion criteria provided clinical testing The PKD1 c.11537+3_11537+5dup variant was identified in 9 of 464 proband chromosomes (frequency: 0.02) from individuals or families with ADPKD, and was not identified in 500 control chromosomes from healthy individuals (Stekrova 2009, Bataille 2011, Reed 2008, Rossetti 2002, Vouk 2006,). The variant was also identified in dbSNP (ID: rs201204878) and ADPKD Mutation Database (classified as likely neutral).This variant was identified in the 1000 Genomes Project in 47 of 5000 chromosomes (frequency: 0.009), NHLBI GO Exome Sequencing Project in 72 of 8226 European American and in 13 of 4246 African American alleles. The variant was also identified in Exome Aggregation Consortium database (March 14, 2016) in 1188 (22 homozygous) of 98342 chromosomes (freq. 0.012) in the following populations: European in 606 of 54618 chromosomes (freq. 0.01), South Asian in 448 of 14506 chromosomes (freq. 0.03), Latino in 76 of 9570 chromosomes (freq. 0.008), Finnish in 32 of 4286 chromosomes (freq. 0.007), African in 10 of 7240 chromosomes (freq. 0.001), East Asian in 1 of 7496 chromosomes (freq. 0.0001) and Other in 15 of 626 chromosomes (freq. 0.02), increasing the likelihood this could be a low frequency benign variant. In addition, the variant was identified with a co-occurring pathogenic PKD1 variant in our lab (p.Ala3571_Val3572del), increasing the likelihood that the c.11537+3_11537+5dup variant does not have clinical significance. The c.11537+3_11537+5dup variant is located in the 5' splice region but does not affect the invariant +1 and +2 positions. However, positions +3 to +6 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. In addition, 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this information is not predictive enough to assume pathogenicity. Population study by Vouk (2006) suggests the variant possibly influences splicing of intron 41, however segregation analysis was not performed due to lack of samples from the family. The case study of the family without history of PKD by Reed (2008) predicted poor match between the variant sequence and consensus splice site with evidence for anticipation, considered to be weak. One population study classified the variant as likely silent (Stekrova 2009) while two other population studies classified the variant as polymorphism (Bataille 2011, Rossetti 2002). In summary, based on the above information, this variant meets our laboratory criteria to be classified as benign.

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