ClinVar Miner

Submissions for variant NM_001009944.3(PKD1):c.4018C>T (p.Arg1340Trp) (rs143690392)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
PreventionGenetics,PreventionGenetics RCV000249037 SCV000305735 likely benign not specified criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000999802 SCV000604725 likely benign Polycystic kidney disease, adult type 2019-04-03 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000712620 SCV000843137 benign not provided 2017-12-21 criteria provided, single submitter clinical testing
GeneDx RCV000712620 SCV001825530 likely benign not provided 2021-02-10 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 22008521, 26489027, 11967008, 22995991, 27499327)
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001292416 SCV001480845 benign Polycystic kidney disease no assertion criteria provided clinical testing The PKD1 p.Arg1340Trp variant was identified in 5 of 328 proband chromosomes (frequency: 0.015) from individuals or families with ADPKD (Bataille 2011, Garcia-Gonzalez 2007, Rossetti 2002, Rossetti 2007). The variant was also identified in dbSNP (ID: rs143690392) as “NA”, and ADPKD Mutation Database (as likely neutral). This variant was identified in the 1000 Genomes Project in 10 of 5000 chromosomes (freq. 0.002), the NHLBI GO Exome Sequencing Project in 35 of 8582 European American alleles (freq. 0.004) and in 5 of 4374 African American alleles (freq. 0.001), the Exome Aggregation Consortium database (August 8, 2016) in 286 (1 homozygous) of 116868 chromosomes (freq. 0.002) in the following populations Finnish in 36 of 6204 chromosomes (freq. 0.006), European (Non-Finnish) in 220 of 63994 chromosomes (freq. 0.003), other in 2 of 838 chromosomes (freq. 0.002), African in 21 of 9516 chromosomes (freq. 0.002), Latino in 6 of 11372 chromosomes (freq. 0.0005), and South Asian in 1 of 16460 chromosomes (freq. 0.00006), but was not seen in East Asian populations, increasing the likelihood this could be a low frequency benign variant. 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 variant was not identified in Clinvitae, ClinVar, GeneInsight COGR, MutDB, PKD1-LOVD, and PKD1-LOVD 3.0. The p.Arg1340 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein. The variant occurs outside of the splicing consensus sequence and 1 in 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a difference in splicing. The variant was identified with a co-occurring pathogenic PKD1 variant p.Leu56ProfsX60, increasing the likelihood that the p.Arg2191His variant does not have clinical significance. In addition, the variant was classified as “a known exonic polymorphism” in multiple studies (Rossetti 2012, Bataille 2011). In summary, based on the above information, this variant meets our laboratory criteria to be classified as benign.
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000712620 SCV001926408 likely benign not provided no assertion criteria provided clinical testing

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